Yeast Cell Wall and Tolerance To Stress

TYPE Review
PUBLISHED 28 July 2022

DOI 10.3389/fmicb.2022.953479
The cell wall and the response

OPEN ACCESS and tolerance to stresses of
EDITED BY
Markus Proft,
Institute of Biomedicine of Valencia
biotechnological relevance in
(CSIC), Spain
REVIEWED BY
yeasts
Javier Arroyo,
Complutense University of Madrid,
Spain Ricardo A. Ribeiro1,2,3 , Nuno Bourbon-Melo1 and
Katy Kao, Isabel Sá-Correia1,2,3*
San Jose State University, United States
Antonio D. Moreno, 1
Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa,
Centro de Investigaciones Energéticas, Lisbon, Portugal, 2 Department of Bioengineering, Instituto Superior Técnico, Universidade
Medioambientales y Tecnológicas, de Lisboa, Lisbon, Portugal, 3 Associate Laboratory i4HB—Institute for Health and Bioeconomy
Spain at Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
*CORRESPONDENCE
Isabel Sá-Correia
[email protected]
SPECIALTY SECTION In industrial settings and processes, yeasts may face multiple adverse
This article was submitted to environmental conditions. These include exposure to non-optimal
Microbial Physiology and Metabolism,
a section of the journal temperatures or pH, osmotic stress, and deleterious concentrations of diverse
Frontiers in Microbiology inhibitory compounds. These toxic chemicals may result from the desired
RECEIVED 26 May 2022 accumulation of added-value bio-products, yeast metabolism, or be present
ACCEPTED 11 July 2022
PUBLISHED 28 July 2022
or derive from the pre-treatment of feedstocks, as in lignocellulosic biomass
hydrolysates. Adaptation and tolerance to industrially relevant stress factors
CITATION
Ribeiro RA, Bourbon-Melo N and involve highly complex and coordinated molecular mechanisms occurring
Sá-Correia I (2022) The cell wall in the yeast cell with repercussions on the performance and economy
and the response and tolerance
to stresses of biotechnological of bioprocesses, or on the microbiological stability and conservation of
relevance in yeasts. foods, beverages, and other goods. To sense, survive, and adapt to different
Front. Microbiol. 13:953479.
doi: 10.3389/fmicb.2022.953479
stresses, yeasts rely on a network of signaling pathways to modulate the
global transcriptional response and elicit coordinated changes in the cell.
COPYRIGHT
© 2022 Ribeiro, Bourbon-Melo and These pathways cooperate and tightly regulate the composition, organization
Sá-Correia. This is an open-access and biophysical properties of the cell wall. The intricacy of the underlying
article distributed under the terms of
the Creative Commons Attribution regulatory networks reflects the major role of the cell wall as the first
License (CC BY). The use, distribution line of defense against a wide range of environmental stresses. However,
or reproduction in other forums is
permitted, provided the original the involvement of cell wall in the adaptation and tolerance of yeasts
author(s) and the copyright owner(s) to multiple stresses of biotechnological relevance has not received the
are credited and that the original
publication in this journal is cited, in
deserved attention. This article provides an overview of the molecular
accordance with accepted academic mechanisms involved in fine-tuning cell wall physicochemical properties
practice. No use, distribution or
during the stress response of Saccharomyces cerevisiae and their implication
reproduction is permitted which does
not comply with these terms. in stress tolerance. The available information for non-conventional yeast
species is also included. These non-Saccharomyces species have recently
been on the focus of very active research to better explore or control
their biotechnological potential envisaging the transition to a sustainable
circular bioeconomy.
KEYWORDS
cell wall, yeasts of biotechnological relevance, stress response, stress tolerance,

signaling pathways
Frontiers in Microbiology 01 frontiersin.org

Ribeiro et al. 10.3389/fmicb.2022.953479
Introduction course of industrial bioprocesses (Klis, 2002; Stewart, 2017).

Considerable cell energy must be invested for maintaining
Saccharomyces cerevisiae is an essential eukaryotic cell such complex and energetically expensive response, considering
model that also has a plethora of industrial applications that over 1200 genes are estimated to be involved, directly
(Parapouli et al., 2020). Since early in human civilization, it or indirectly, in cell wall synthesis and regulation (De Groot
has been extensively used in the production of fermented et al., 2001). A deeper mechanistic insight into how the cell
food and beverages, which nowadays include bread, chocolate, enacts such changes at the level of the cell wall is expected
wine, beer, cider, sake, spirits (rum, vodka, whisky, brandy), to lead to a better understanding of yeast’s adaptation to
and other alcoholic beverages arising from the fermentation stresses of industrial relevance that ultimately may lead to
of fruits, honey, and tea (Walker and Stewart, 2016; Parapouli improved bioprocess productivity and product yield. This
et al., 2020). Nowadays, many enzymes, pharmaceuticals, understanding is also instrumental to guide the improvement
nutraceuticals, and other added-value bioproducts can be of food preservation practices, in particular those involving
produced in engineered yeast cell factories (Borodina and the use of weak acid food preservatives, temperature- and
Nielsen, 2014; Runguphan and Keasling, 2014; Kwak and Jin, osmotic- induced-stresses for the microbiological stabilization
2017; Nielsen, 2019; Fathi et al., 2021; Wang et al., 2021; and conservation of foods, beverages, and other goods.
Arnesen et al., 2022; Stovicek et al., 2022). The implementation The suggested role for the cell wall in yeast stress
of a sustainable circular bioeconomy requires the development response and tolerance, mostly emerged from the datasets
of Advanced Yeast Biorefineries to produce biofuels (e.g., obtained from the numerous genome-wide expression analyses
bioethanol and biodiesel), chemicals, materials, and other or chemogenomic analyses under stress reported in recent
bioproducts from organic residues from agriculture, forestry, years. However, the cell wall has not received the attention it
and industry residues (Madhavan et al., 2017; Mukherjee deserves as a tolerance determinant toward multiple stresses.
et al., 2017; Yamakawa et al., 2018; Panahi et al., 2019; Saini The objective of this review paper is to gather the literature
and Sharma, 2021; Usmani et al., 2021; Raj et al., 2022). available on the topic and provide a critical opinion and a
For the transition to a sustainable biobased economy, the comprehensive view on the current knowledge on the role of the
use of non-conventional yeasts is gaining momentum since cell wall and related signaling pathways in yeast adaptation and
strains of this heterogenous group of non-Saccharomyces species survival under industrially relevant stresses. Attempts of stress
are advantageous alternatives to S. cerevisiae whenever they tolerance improvement through the manipulation of cell wall
can natively express highly interesting metabolic pathways, biosynthetic pathway are also included. Most of the published
assimilate a wider range of carbon sources, and/or exhibit higher knowledge pertains to the yeast model S. cerevisiae but the
tolerance to relevant bioprocess-related stresses (Thorwall et al., information available in the scientific literature for other yeast
2020). Non-conventional yeasts are also being explored to species of biotechnological relevance is also offered.
enhance the flavor profiles and reduce the ethanol content
of alcoholic beverages (Gschaedler, 2017; Holt et al., 2018;
Bourbon-Melo et al., 2021). Spoilage yeasts, as is the case of the
osmophilic and highly weak acid tolerant yeast species of the
The yeast cell wall: composition,
Zygosaccharomyces genera, are also being studied due to their structure, function, and
high tolerance to stresses associated to food preservation (Palma biosynthesis
and Sá-Correia, 2019). However, the advanced genome-editing
techniques and other genomic and bioinformatics information The cell wall of S. cerevisiae represents up to 30% of the
and tools available for S. cerevisiae, are arguably the major cell’s dry weight (w/w) being almost entirely composed of
reason why this species is still considered the major yeast cell polysaccharides (≈85%) and proteins (≈15%) (Nguyen et al.,
factory (Nandy and Srivastava, 2018; Nielsen, 2019). 1998) with a thickness of 115—120 nm, as determined by atomic
Regardless of the yeast species or the specific application, force microscopy and ultrathin-sectioning electron microscopy
industrial yeasts typically encounter stresses that trigger (Dupres et al., 2010; Yamaguchi et al., 2011). It is a layered
intricate cellular responses involving multiple players (Bauer structure with two different layers (Figure 1), distinguishable
and Pretorius, 2000; Gibson et al., 2007; Eardley and Timson, by ultrathin-sectioning electron microscopy (Hagen et al., 2004;
2020). Among these players is the cell wall. The cell wall Yamaguchi et al., 2011; Orlean, 2012). The electron-dense
maintains cell shape and integrity and, together with the plasma outer layer mostly consists of mannoproteins whereas, in the
membrane, is part of the cell envelope and the first line more electron-transparent inner layer, glucans are the major
of defense against multiple adverse environmental conditions component and chitin is in a lesser extent (Hagen et al.,
(Stewart, 2017). The cell wall is a highly dynamic organelle 2004; Yamaguchi et al., 2011; Orlean, 2012). Most of the
whose biochemical and biophysical properties can be finely cell wall mechanical strength derives from its inner layer, in
tuned as yeast cells encounter different stresses throughout the which the β-linked glucans are the major components of the

polysaccharide fraction, and alone represent 30–60% of the There are two major classes of CWPs, namely the
cell wall dry weight (Fleet, 1991). Approximately 30–60% of glycosylphosphatidylinositol CWPs (GPI-CWPs), and the
the cell wall dry biomass is composed by β-glucans, around alkali-sensitive linkage CWPs (ASL-CWPs), which include
85% of these are 1,3-β-glucans and the remaining are 1,6- proteins of the internal repeats (Pir) family (Klis, 2002; Klis
β-glucans (Aguilar-Uscanga and François, 2003; Orlean, 2012; et al., 2006; Figure 1). While GPI-CWPs are typically linked
Figure 1). The β1,3-glucan chains are composed of ≈1500 to β1,6-chains by a GPI anchor, ASL-CWPs are directly linked
glucose units and are assembled in coiled spring-like structure to β1,3-glucans through an alkali-labile bond (Lesage and
that confer elasticity and tensile strength to the cell wall Bussey, 2006). They also differ in their distribution throughout
(Klis, 2002). The β1,6-glucans chains are shorter than the the cell wall. While GPI-CWPs are found in the outer layer,
β1,3-glucan chains and, although quantitatively being a minor Pir-CWPs seem to be uniformly distributed throughout the
component of the wall, β1,6-glucans have a central role in cross- inner layer, which is consistent with their direct association with
linking β1,3-glucans together (Kollár et al., 1997; Orlean, 2012). β1,3-glucans (Kapteyn et al., 1999b; Klis et al., 2006; Figure 1).
Additionally, β1,6-glucans can be connected to mannoproteins Cell wall biogenesis involves cell wall polysaccharide
with a glycosylphosphatidylinositol (GPI) anchor and to chitin synthases and enzymes involved in cell wall remodeling,
(Kollár et al., 1995; Orlean, 2012). The reducing ends of β1,3- assembly and degradation (Klis et al., 2006; Free, 2013;
glucans chains can be linked to a side-branching β1,6-glucan Figure 2). The β1,3-glucans are synthetized as a linear polymer
on β1,3-glucans chains, forming a fibrillar structure that serves by the FKS family of genes (FKS1-3). The FKS1 and FKS2
as backbone and anchorage point for other constituents of the genes code for β1,3-glucan synthases and differ mostly on the
cell wall (Lesage and Bussey, 2006; Figure 1). The non-reducing expression pattern, whereas FKS3 remains poorly characterized
ends of 1,3-β-glucans are linked to the reducing ends of chitin (Garrett-Engele et al., 1995; Mazur et al., 1995; Igual et al.,
through a β-1,4 link (Kollár et al., 1995, 1997; Orlean, 2012). 1996; Zhao et al., 1998; Lesage and Bussey, 2006). While FKS1
Chitin is a linear polymer of β1,4-linked expression is prevalent under optimal growth, FKS2 expression
N-acetylglucosamine (GlcNAc), representing less than 2% is induced in response to different stresses such as glucose
of S. cerevisiae cell wall dry weight (Figure 1). Chitin can occur depletion, alternative carbon sources (e.g., acetate, glycerol,
both in the free form, or bound to β-glucans (Kollár et al., galactose), high extracellular Ca2+ or heat stress (Garrett-
1995, 1997; Orlean, 2012). Chitin is normally concentrated as a Engele et al., 1995; Mazur et al., 1995; Igual et al., 1996;
ring between the mother cell and the emerging bud and in the Zhao et al., 1998). Several genes influence β-1,6-glucan levels,
lateral walls of the mother cell after septation (Cabib, 2009). In in particular the KRE6 and SKN1 genes, encoding proteins
response to stress, chitin levels can increase to as much as 20% involved in β1,6-glucan synthesis, and the KRE9 and KHN1
of the cell wall dry weight (Popolo et al., 1997; Dallies et al., encoding CWPs presumably involved in β1,6-glucan cross-link
1998; Ram et al., 1998; Osmond et al., 1999; Valdivieso et al., to other components of the cell wall (Roemer et al., 1994; Lesage
2000; Magnelli et al., 2002; Orlean, 2012). Changes occurring and Bussey, 2006). Chitin is synthetized as a linear polymer by
in cell wall nanomechanical properties, such as cell surface the chitin synthases encoded by the CHS1-3 gene family. The
stiffness, are mostly dependent on the crosslinking between gene CHS3, encoding chitin synthase III, is by far responsible
β-glucans and chitin (Dague et al., 2010) and occur in response for the majority of chitin synthesis, whether it is during
to stresses of industrial relevance (Dague et al., 2010; Pillet et al., optimal growth conditions or during stress response when
2014; Schiavone et al., 2016; Ribeiro et al., 2021, 2022). increased chitin deposition in the cell wall occurs (Roncero,
The outer layer is composed by cell wall mannoproteins 2002; Klis et al., 2006; Lesage and Bussey, 2006; Orlean, 2012).
(Figure 1). These mannoproteins are heavily glycosylated, Also, CWPs mannosylation requires several genes encoding
modified with both N-and O-linked carbohydrates, commonly proteins with mannosyltransferase activity (Gonzalez et al.,
formed by mannose (Klis et al., 2006; Schiavone et al., 2014). 2009a; Orlean, 2012). The GAS family (GAS1-5), encodes β1,3-
The outer layer serves an important protective role in the cell glucanosyltransferases involved in β1,3-glucan branching and
by limiting the access of external aggressors, such as foreign elongation, in which GAS1 has a major role and is also required
enzymes, to the inner layer (Klis et al., 2006). The proteins for β1,6-glucan linkage with β1,3-glucan chains (Ram et al.,
that constitute this layer are involved in a wide range of 1998; Ragni et al., 2007; Orlean, 2012; Aimanianda et al.,
functions often related to cell-to-cell interactions (e.g., mating, 2017). Shortening of glucan chains is also required for cell wall
flocculation, biofilm formation, etc.) (Klis, 2002). Increased cell remodeling and involves BGL2 and EXG1-2 encoding a major
wall hydrophobicity influences flocculation leading to increased endoglucanase and major exoglucanases, respectively (Larriba
robustness to inhibitory chemical compounds (Kahar et al., et al., 1995; Lesage and Bussey, 2006; Orlean, 2012; Aimanianda
2022). This was associated with changes in the expression of et al., 2017). The transglycosylases GPI proteins encoded by the
MOT3 gene, encoding a transcription regulator that controls the CRH1-2 genes have a major role in the cross-linkage between
expression of a cell wall protein (CWPs) encoding gene, YGP1, chitin and glucans (Cabib et al., 2007, 2008; Cabib, 2009; Orlean,
that influences cell wall hydrophobicity (Kahar et al., 2022). 2012; Blanco et al., 2015). Endochitinases, encoded by CTS1-2,

FIGURE 1
Schematic representation of S. cerevisiae cell wall. The inner layer of the cell wall is mostly composed of β1,3-glucan chains branched with
β1,6-glucans, and chitin. The outer layer is composed of mannoproteins, most of which are linked to the inner wall by a GPI anchor, whereas
ASL-Pir proteins seem to be uniformly distributed throughout the inner layer. ASL-CWP, alkali-sensitive linkage cell wall protein. GPI-CWP,
glycosylphosphatidylinositol cell wall protein. Details in the main text.
are required for septation and cell separation (Kuranda and in response to environmental external stimuli that may damage
Robbins, 1991; Cabib et al., 1992; Orlean, 2012). the cell wall (Gustin et al., 1998; Levin, 2011; Sanz et al., 2018;
Saccharomyces cerevisiae cell wall appears to have many Figure 2). CWI pathway relies on a family of plasma membrane
organizational similarities with the walls of other ascomycetous sensors, namely Wsc1-3, Mid2, and Mtl1. Stimuli that may
yeasts and even of basidiomycetous yeasts (Jaafar and Zueco, impose a stress to the cell are detected by these sensors and
2004; De Groot et al., 2005, 2008; Patel and Free, 2019; Garcia- triggers a phosphorylation cascade that elicit transcriptional
Rubio et al., 2020). However, there are differences between the changes to enable the cell to adapt to stress conditions (Kock
cell walls of S. cerevisiae and other fungi. For instance, the et al., 2016; Sanz et al., 2018; Figure 2). For the Wsc1 sensor,
cell wall of S. cerevisiae does not contain α-glucans, chitosan, the signaling transduction to the downstream components of
or melanin, and its chitin content is relatively low, especially the pathway is influenced by the spatial distribution of these
when compared to other yeasts or filamentous fungi (e.g., sensors within the plasma membrane, requiring a functional
Candida albicans, Aspergillus niger, Paracoccidioides brasiliensis, extracellular cysteine-rich domain to form clusters in specific
Blastomyces dermatitidis) (Kanetsuna et al., 1969; Garcia-Rubio microdomains or rafts (Heinisch et al., 2010; Schöppner
et al., 2020; van Leeuwe et al., 2020). et al., 2022). Industrially relevant stresses reported to trigger
a response by the referred CWI pathway membrane sensors
are highlighted in Table 1. Together with phosphatidylinositol
4,5-biphosphate, PIP2 , which recruits the guanine nucleotide
Cell wall-related signaling exchange factors (GEFs) Rom1 and Rom2, the surface sensors
pathways induced by stress activate the Rho1 GTPase (Levin, 2011; Sanz et al., 2018). Rho1
regulates both β1,3-glucan synthases encoded by FKS1 and
Yeast cells sense and respond to environmental stresses FKS2, and β1,6-glucan synthase activities, and is considered a
through the induction and activity of different signaling key regulator of CWI signaling (Levin, 2011). Rho1 activates
pathways (Chen and Thorner, 2007). Depending on the type Pkc1 and sets in motion a series of phosphorylation events
of stress, specific pathways can be triggered and directly, or which sequentially activate Bck1, Mkk1/2, and the pathway’s
indirectly, elicit changes in the composition and architecture of MAPK, Slt2 (Levin, 2011; Figure 2). Finally, Slt2 activates
the cell wall (Levin, 2011; Figure 2). The CWI signaling pathway two transcription factors, Rlm1 and SBF (Swi4/Swi6 complex),
is one of the most well-described pathways, characterized for that coordinate the CWI transcriptional response (Levin, 2011;
its role in cell wall maintenance and homeostasis, particularly Orlean, 2012; Figure 2). This response mostly involves the

FIGURE 2
Schematic representation of the CWI, HOG, and calcineurin signaling pathways and interactions. The cell wall integrity pathway (CWI), in blue, is
the main pathway involved in the maintenance of yeast cell wall integrity. It is frequently activated by a signal starting at plasma membrane
sensors (Wsc1-3, Mid2, Mtl1), which then trigger a cascade culminating in the phosphorylation of Slt2. Phosphorylated Slt2 activates the
transcription factor Rlm1 and the SBF complex (Swi4/6), triggering a transcriptional response that elicit changes at cell wall level.
Phosphoinositide synthesis (in orange) plays an important role in the activation of the CWI pathway by recruiting Rom1/2 to the plasma
membrane, which activates the main regulator of the pathway, the GTPase Rho1. The CWI pathway receives input and interplays with other
pathways, including the high osmolarity glycerol (HOG) pathway (in green) and the calcineurin pathway (in pink), represented in the figure, but
also with the protein kinase A (PKA) and TOR signaling pathways. Details in the text.
activation of cell wall biogenesis genes. The Rlm1 transcription revealed for other yeast species (Donlin et al., 2014; Valiante
factor is responsible for the expression of most of the genes et al., 2015; Madrid et al., 2016; Assis et al., 2018).
induced in response to cell wall stress, such as the CHS3 gene, Changes occurring at the level of plasma membrane can also
and also regulates the expression of FKS1 (Jung and Levin, 1999; elicit responses at the level of the cell wall. Plasma membrane
Klis et al., 2006). Importantly, Rlm1 activates MLP1, coding for stretching appears to be the main factor in activating the
a Slt2 pseudo-kinase paralog, that, together with Slt2, activates CWI pathway in response to a number of stresses, including
the SBF complex for transcription of a subset of cell wall stress- high osmotic pressure and supra-optimal temperature (Kamada
activated genes. Among them are genes related with glucan et al., 1995; Hohmann, 2002b). This is consistent with the CWI
synthesis (FKS1, FKS2) or glucan elongation and branching pathway-activating sensors being located at the membrane and
(GAS1) (Igual et al., 1996; Baetz et al., 2001; Kim et al., 2008; the likely role of Wsc1 as a mechanosensor (Kock et al., 2015).
Levin, 2011; Harris et al., 2013)This brief description of the CWI Alterations of plasma membrane lipid composition have also
pathway as a simple linear cascade of events can be deceiving. In been shown to impact the CWI pathway, namely, a defective
fact, the CWI pathway receives lateral influences from cAMP- biosynthesis of the complex sphingolipid mannosylinositol
Protein Kinase A (PKA) signaling, TOR signaling, calcineurin phosphorylceramide (MIPC) leads to increased abundance of
signaling, the HOG pathway, and likely from others not yet the phosphorylated form of Slt2 and sensitivity to cell wall-
clarified (Fuchs and Mylonakis, 2009; Rodríguez-Peña et al., perturbing agents (Morimoto and Tani, 2015). This phenotype is
2010; García et al., 2017; Udom et al., 2019; Jiménez-Gutiérrez partly suppressed by the upregulation of ergosterol biosynthesis,
et al., 2020a,b; Figure 2). This complex network is what enables suggesting that MIPC and ergosterol are coordinately involved
the CWI pathway to be activated by numerous types of stressors, in maintaining the integrity of the cell wall (Tanaka and Tani,
ensuring an adequate response to each stress or group of 2018). Also, a reported crosstalk between plasma membrane
stresses (Figure 2). The existence of a complex interplay between ergosterol content (related with the level of expression of the
the CWI pathway and other signaling pathways is also being plasma membrane ergosterol transporter Pdr18), and cell wall

TABLE 1 Cell wall integrity membrane sensors implicated in the ethanol, acetic acid or lactic acid lead to oxidative stress
sensing of industrially relevant stresses.
that occurs when cellular defense mechanisms are unable to
CWI membrane Industrially relevant Bibliographic cope with existing ROS (Costa and Moradas-Ferreira, 2001;
sensor stress references Abbott et al., 2009; Teixeira et al., 2009; Morano et al., 2012;
Charoenbhakdi et al., 2016).
Wsc1 Hyper-osmolorarity García-Rodríguez et al.,
Heat 2005 The cell wall or, more broadly, the cell envelope, has
Acetic acid Rajavel et al., 1999 been associated with oxidative stress toxicity and tolerance.
Alkaline pH Mollapour et al., 2009
Diamide and H2 O2 Serrano et al., 2006;
This involvement has been unveiled by studies focused on
Kwon et al., 2016 S. cerevisiae exposure to pro-oxidant agents such as hydrogen
Vilella et al., 2005 peroxide, lipid hyperoxides, diamine, catecholamines, and
Wsc2 H2 O2 Vélez-Segarra et al., 2020 organic hydroperoxides, such as cumene hydroperoxide (CHP)
Wsc1/Wsc2 Impaired mannosylinositol Tanaka and Tani, 2018 and linoleic acid hydroperoxide (LoaOOH) (Staleva et al.,
phosphorylceramide
metabolism 2004; Vilella et al., 2005; Petkova et al., 2010; Taymaz-Nikerel
Mid2 Hyper-osmolorarity García-Rodríguez et al., et al., 2016). Oxidative stress resulting from exposure to
Heat 2005 these agents induces distinct responses in S. cerevisiae. For
Low pH – media acidified Rajavel et al., 1999
instance, a quantitative proteomics study reported differences
with a strong acid Claret et al., 2005
H2 O2 Jin et al., 2013 in the activation of the CWI pathway between hydrogen
peroxide, CHP and diamide (Pandey et al., 2020). Decreased
Mtl1 Diamide and H2 O2 Vilella et al., 2005; cell permeability, a property influenced by the thickness and
Jin et al., 2013
composition of the cell wall and plasma membrane, results in
increased resistance to pro-oxidant compounds by limiting their
biophysical properties suggested a coordinated response to diffusion into the cell (Sousa-Lopes et al., 2004). Furthermore,
counteract acetic acid deleterious effects, reinforcing the notion membrane lipid composition is a determinant of oxidative stress
that plasma membrane lipid composition influences cell wall resistance, with cells containing a higher level of saturated fatty
integrity during stress (Ribeiro et al., 2022). acids being more resistant than cells with a higher level of
For the main and better studied stresses encountered polyunsaturated fatty acids (Jamieson, 1998).
during industrial bioprocesses, this review provides, whenever Diamide induces the formation of disulfide bonds in the
possible, an integrative view of the pathways and responses that three-dimensional structure of CWPs, causing changes in the
cooperatively maintain cell wall integrity and, in so doing, helps morphology of the cell outer layer and the increase of cell
yeasts to resist to multiple stresses. wall thickness (De Souza Pereira and Geibel, 1999; Vilella
et al., 2005). CHP causes oxidative damage to the cell wall
periphery leading to the upregulation of genes related to cell
Yeast response and tolerance to wall biogenesis (HSP150), CWI pathway regulation (RHO1,
ROM2) and β1,6-glucan synthesis (KRE5, KRE6, KHN1) (Sha
industrially relevant stresses et al., 2013; Figure 3). The transcriptional reprogramming of
involving the cell wall yeast in response to oxidative stress is mainly regulated by
two oxidative stress-responsive transcription factors, Yap1 and
The cell wall in the response to Skn7, and the general stress transcription factors, Msn2/Msn4
oxidative stress (Auesukaree, 2017). Notably, Skn7 has an important role in the
regulation of genes involved in the maintenance of cell wall
All aerobically growing organisms suffer exposure to integrity, including genes coding for CWPs (Alloush et al., 2002;
oxidative stress, caused by reactive oxygen species (ROS) Li et al., 2002; Levin, 2011). The CWI pathway sensors Wsc1,
capable of damaging cellular DNA, lipids, carbohydrates, and Wsc2, Mtl1, and Mid2 play an important role in the sensing of
proteins, threatening cell integrity (Jiménez-Gutiérrez et al., oxidative stress induced by H2 O2 (Vilella et al., 2005; Jin et al.,
2020b). Consequently, mechanisms to protect cell components 2013; Vélez-Segarra et al., 2020). Surviving and overcoming
against ROS were evolved and the antioxidant defenses can oxidative stress induced by H2 O2 , as for diamine, requires Pkc1
be induced either by respiratory growth or in the presence of and the upstream element of the CWI pathway Rom2 (Vilella
pro-oxidants (Moradas-Ferreira and Costa, 2000). Yeasts have et al., 2005; Figure 3).
several inducible adaptive stress responses to oxidants regulated In Yarrowia lipolytica, a promising oleaginous yeast
at the transcriptional and posttranscriptional levels (Jamieson, (Ledesma-Amaro and Nicaud, 2016), oxidative stress induced
1998; Moradas-Ferreira and Costa, 2000). Stresses commonly by H2 O2 leads to changes in the morphology of the cell
arising during industrial fermentations, such as supra-optimal wall, with the formation of globular surface structures in the
temperatures or presence of inhibitory concentrations of cell wall surface (Arinbasarova et al., 2018). When exposed

FIGURE 3
Schematic model of the described S. cerevisiae adaptive responses common to multiple industrial relevant stresses involving the cell wall. The
cell wall integrity pathway (CWI) and other signaling pathways (HOG and Calcineurin pathway) that, in collaboration with the CWI pathway and
the upregulation of cell wall genes, lead to changes in the composition and nanomechanical properties of the cell wall in response to different
stresses are highlighted. Squares of different colors indicate the different industrial-relevant stresses for which data is available in the literature.
to soluble complexes of UO2, the mRNA levels from genes of cellular turgor (Davenport et al., 1995; Hohmann, 2002a).
involved in elongation of β1,3-glucan and chitin synthesis Although there are many similarities in how the yeast cell
were reduced in a tropical marine strain of Y. lipolytica, able responds to osmotic stress caused by different agents, thus
to immobilize in the cell surface uranium often associated allowing the description of a generalized stress response, there
with oxidative stress (Kolhe et al., 2020). These complexes, are also specific features for each osmolyte or salt stress
formed above pH 7.0, are prevalent in aquatic environments (Gonzalez et al., 2016).
such as rivers or sea water, being this strain considered Sudden exposure to increased osmolarity leads to cell
promising for the bioremediation of uranium-contaminated shrinkage due to water efflux and likely causes the release of
aquatic environments (Kolhe et al., 2020, 2021). plasma membrane material, as well as changes in cell wall
structure (Morris et al., 1983; Claro et al., 2007; Saldaña et al.,
2021). The decrease in cell volume is accompanied by changes
Osmotic stress in cell morphology and surface roughness (Adya et al., 2006;
Saldaña et al., 2021). Intracellularly, a compensatory response is
Hyper-osmotic stress is common in industrial bioprocesses triggered, recruiting water from the vacuole into the cytoplasm
(Mattanovich et al., 2004). Very high gravity fermentations are (Mager and Siderius, 2002). These changes occur immediately
frequently used to enhance product titres in specific sectors, after an osmotic upshift, likely caused by rapid biophysical forces
such as in first-generation bioethanol production by increasing (Ene et al., 2015). To survive such a shock, the properties of
initial sugar concentration and, consequently, osmotic pressure the cell wall have to be modified to have enough elasticity
(Deparis et al., 2017). In winemaking and baking, yeasts to respond to shifts in osmolarity, while maintaining enough
also have to grow in hyper-osmotic environments and their rigidity to preserve cell morphology and integrity (Ene et al.,
performance depends on the ability to adapt and respond 2015). The rapid changes of cellular volume and shape occurring
to this stress (Attfield and Kletsas, 2000; Noti et al., 2015). in response to hyperosmotic shock that are fully reversible when
Also, the increase of osmotic pressure induced by the addition cells are introduced in an isosmotic solution, are evidences of
of stressful concentrations of sugars or salts is beneficial for the remarkable plasticity of the cell wall (Saldaña et al., 2021).
food preservation (Gonzalez et al., 2016). In yeasts, the High The HOG pathway (Figures 2, 3) is a MAPK signal
Osmolarity Glycerol (HOG) and the CWI signaling pathways transduction system and the major pathway in the adaptation
are central to osmotic stress-induced response and control of yeast cells to increased osmolarity (Hohmann, 2002a). The

pathway relies on two osmolarity sensors, Sln1 and Sho1. During of ZrFPS1 (Pøibylová et al., 2007; Hou et al., 2013; Guo
an osmotic upshift, Sln1 is transiently inhibited, diminishing the et al., 2020). Among Z. rouxii upregulated genes under high
levels of phosphorylated Ssk1. Unphosphorylated Ssk1 can then osmolarity stress are FKS1(encoding a β1,3-glucan synthase),
interact with Ssk2/Ssk22, which in turn phosphorylates Pbs2. UTR2 (encoding a cell wall transglycosylase), KRE9 (encoding
The Sho1 osmosensor also transmits a signal to Pbs2 via the a glycoprotein involved in β-glucan assembly), CHS1 (encoding
MAPKKK Ste11 (Hohmann, 2009). The phosphorylated Pbs2 a chitin synthase) and KAR2 (encoding an ATPase involved
activates Hog1 and modulates the expression of several genes β1,6-glucan synthesis and also involved in the translocation of
(Hohmann, 2009), including the transcriptional activation proteins into the endoplasmic reticulum) (Guo et al., 2020). The
of GPD1 and GPP2 genes, encoding a glycerol 3-phosphate upregulation of the encoding genes helps to explain why the cell
dehydrogenase and a glycerol-1-phosphatase respectively, wall became thicker as the cell volume decreases, resulting in a
involved in glycerol production (Hohmann, 2009). In response smaller amplitude of cell size variation (Guo et al., 2020).
to hyper-osmotic stress, Hog1 phosphorylates Rgc2, a regulator In a Zygosaccharomyces mellis strain, isolated from honey
of the Fps1 glycerol channel, causing the dissociation of Rgc2 and tolerant to high-glucose concentrations (Liu et al., 2016,
from Fps1 and the consequent glycerol channel closure (Lee 2021), the genes KRE5 (involved in β1,6-glucan synthesis) and
et al., 2013). Together, the blockade of glycerol efflux by SLT2 (encoding a kinase of the CWI pathway), are upregulated
the closing of the Fps1 channel and the increase in glycerol under hyper-osmotic stress (Liu et al., 2021). This indicates that,
biosynthetic capacity lead to glycerol accumulation in the in Z. mellis, the maintenance of cell wall integrity under this
cytoplasm and effectively counteract the loss of turgor pressure stress is also important. In D. hansenii, the cell wall was also
caused by an osmotic upshift (Jiménez-Gutiérrez et al., 2020b). shown to play a critical role in osmosensing and genes involved
A coordinated interplay between the HOG pathway and the in CWP mannosylation (MNN1, PMT2, PSA1, and MNT1) are
CWI pathway allows yeast cells to better adapt to hyper-osmotic upregulated in response to hyper-osmotic stress (Thomé, 2007;
stress conditions (García-Rodríguez et al., 2005; Vaz et al., 2020; Gonzalez et al., 2009b).
Figure 3). The CWI pathway appears to be indirectly activated
by an increase in turgor pressure caused by the accumulation
of glycerol, leading to transient phosphorylation of Slt2 that Heat stress
depends on a functional HOG pathway (García-Rodríguez et al.,
2005). Nevertheless, the CWI sensors Mid2 and Wsc1 seem Another obstacle that can be faced by yeast cell factories
to be involved in the sensing of Hog1-driven accumulation of is temperature stress, in particular heat stress. Heat stress is
glycerol (García-Rodríguez et al., 2005). Further evidences of common during alcoholic fermentations to produce alcoholic
the interplay between the HOG pathway and the CWI pathway beverages or bioethanol due to their exothermic nature. If the
were reported (Vaz et al., 2020). Chemogenomic studies have temperature is not controlled, a significant rise in temperature
implicated genes related to β1,3-glucan synthesis (FKS1), β1,6- occurs (Parapouli et al., 2020; Walker and Basso, 2020).
glucan synthesis (KRE6) and cell wall mannosylation (MNN10, Given that in the presence of other stresses, in particular of
ANP1) as determinants of tolerance to high-glucose and sucrose ethanol or acetic acid stress, the optimum and the maximum
concentrations (Ando et al., 2006; Teixeira et al., 2010), known temperatures for growth decrease as the stress level increase,
to induce hyper-osmotic stress (Deparis et al., 2017). even temperatures close to the optimal range of growth
In Y. lipolytica, hyper-osmotic stress was also found to can become lethal temperatures, depending on the level of
lead to cell wall remodeling (Kubiak-Szymendera et al., 2022). stress (van Uden, 1985; Godinho et al., 2021). Despite the
YlHOG1 deletion impacts filamentous growth, cytokinesis, and importance of cold stress, the related literature is scarce in the
resistance to cell wall perturbing agents (Rzechonek et al., context of this review, so this part of the article is essentially
2018). A quantitative proteomic analysis has shown that, dedicated to heat stress.
among the upregulated proteins under hyper-osmotic stress is At supra-optimal temperatures in the absence of any other
Pil1, involved in formation of membrane-associated protein stress (higher than 35–37◦ C), S. cerevisiae activates the heat
complexes commonly referred as eisosomes and distributed shock response (HSR) and undergoes physiological changes
across the cell surface periphery, and UTR2 coding for a CWP, which include membrane and cell wall restructuring (Verghese
involved in glucan-chitin crosslinking in S. cerevisiae (Kubiak- et al., 2012; Schiavone et al., 2014). During heat stress, β1,6-
Szymendera et al., 2022). Other non-Saccharomyces species, glucan and chitin content increases by 20 and 100% respectively,
such as Zygosaccharomyces rouxii, Debaryomyces hansenii, and and β1,3-glucans levels decrease by 45% (Schiavone et al.,
Pichia sorbitophila are notable for their osmotolerance (Bubnová 2014; Figure 3). The increased β1,6-glucan synthesis under heat
et al., 2014). The spoilage yeast of high-sugar or high-salt stress is in accordance with a higher number of cross-linkages
foods Z. rouxii appears to react to hyperosmolarity similarly between this polymer and chitin, presumably compensating
to S. cerevisiae, accumulating intracellular glycerol through cell wall weakening during this stress (Kapteyn et al., 1999a;
the increased expression of ZrGPS1 and decreased expression Schiavone et al., 2014). Heat stress also induces changes in

the morphology of the yeast cell surface with the formation of often required to allow an adequate fermentative performance
circular structures in the surface of heat-stressed cells (Pillet (Lehnen et al., 2019; Thorwall et al., 2020). Two prominent
et al., 2014). The emergence of these structures is, apparently, examples of thermotolerant yeast species, shown to be able to
related to a dysfunction in the budding machinery, accompanied grow relatively well above 40◦ C, are Kluyveromyces marxianus
by a concomitant increase in chitin and cell wall stiffness, and Ogataea polymorpha (formerly Hansenula polymorpha)
regulated by the CWI pathway (Pillet et al., 2014; Figure 3) (Lehnen et al., 2019; Thorwall et al., 2020). In K. marxianus,
activated in response to heat stress (Torres et al., 1991; Lee high temperatures were shown to lead to upregulation of genes
and Levin, 1992; Irie et al., 1993). Together with Msn2/4, associated with changes in plasma membrane composition (Fu
Hsf1 is a transcription factor responsible for the bulk of the et al., 2019). Very few is reported concerning changes occurring
HSR (Imazu and Sakurai, 2005; Truman et al., 2007). Heat in K. marxianus cell wall under heat stress but a strain isolated
stress also promotes glycerol efflux by the opening of Fps1 from agave when grown at 42◦ C exhibit increased sensitivity
channels regulated by the CWI pathway (Dunayevich et al., to lyticase than when grown at 30◦ C, indicating that heat
2018). The resulting turgor loss stimulates the activation of stress may affect cell wall integrity (Castillo-Plata et al., 2021).
the HOG pathway, promoting glycerol production and the In Ogataea species, thermotolerance has been attributed to
re-establishment of turgor pressure (Dunayevich et al., 2018). a structural predisposition of the cell envelope, related with
Heat shock leads to the intracellular accumulation of trehalose membrane and cell wall composition, allowing a higher cell
in S. cerevisiae (Attfield, 1987; Hottiger et al., 1987). Since envelope stability (Lehnen et al., 2019). Among the candidate
trehalose and thermotolerance are closely related, trehalose was genes that contribute to heat tolerance in O. polymorpha is
suggested to act as a thermoprotectant (Hottiger et al., 1989). an ortholog of S. cerevisiae PSA1, coding for GPD-mannose
The intracellular accumulation of trehalose causes a decrease pyrophosphorylase, involved in cell wall biosynthesis (Seike
of the specific growth rate that may trigger the environmental et al., 2021). In the genus Ogataea, Mpk1 appears to be involved
stress response (ESR) and higher thermotolerance (Gibney in CWI signaling in response to heat stress, but, different
et al., 2015). The accumulation of trehalose increases cytosolic Ogataea strains exhibit different growth phenotypes when
osmolarity and turgor pressure, mimicking hypotonic stress, MPK1 is absent (Kim et al., 2018). Compared to O. polymorpha,
and causing plasma membrane stretching known to lead O. parapolymorpha has a thinner β-glucan and chitin layer
to activation of the CWI pathway (Kamada et al., 1995; with short mannan chains and the derived deletion mutant
Mensonides et al., 2005). Consistently, preventing trehalose mpk11 exhibit more severe growth defects during heat stress
synthesis by deletion of the TPS1 gene led to decreased and higher susceptibility to cell wall-perturbing agents, leading
activation of the CWI pathway upon exposure of yeast cells the authors to consider these differences related to cell wall
to heat stress (Mensonides et al., 2005). Interestingly, a recent structural differences (Kim et al., 2018).
study suggests that the UDP-Glucose Pyrophosphorylase Ugp1 The characterization of the yeast response to low
is required for heat stress response by influencing trehalose and temperatures is also important in industry-related bioprocesses
glucan content (Zhang and Xu, 2021). (Liszkowska and Berlowska, 2021), in particular in many wine
Although the mechanism behind heat-induced activation and beer fermentations, resulting in the retention of more
of the CWI pathway is not clear, the Wsc1 and Mid2 CWI volatile compounds that influence the sensory properties of
sensors appear to be involved in the activation of CWI pathway, the product (Liszkowska and Berlowska, 2021). Furthermore,
reinforcing the notion that this stress is ultimately transmitted cold-adapted spoilage yeasts can potentially impose health risks
to the cell surface (Verna et al., 1997; Rajavel et al., 1999; Martín to the consumers and economic burden in the Food industry,
et al., 2000; Levin, 2011; Verghese et al., 2012). In fact, Wsc1 being able to grow and proliferate at temperatures at which
sensors form clusters in the plasma membrane upon heat stress food products are refrigerated (Fleet, 2011). Among the genes
(the so-called Wsc1 sensosomes) enhancing the CWI pathway that are upregulated in response to cold temperatures are genes
signaling capability (Heinisch et al., 2010). The expression of the encoding cell wall mannoproteins (TIR1-2, TIR4, TIP1, and
CWI pathway SLT2 gene, the HSP150 gene encoding a protein DAN1) (Abramova et al., 2001; Sahara et al., 2002; Homma
required for cell stability and the CWP-encoding gene YGP1 et al., 2003; Schade et al., 2004; Murata et al., 2006; Abe, 2007;
are induced in response to heat stress (Causton et al., 2001; Figure 3). Increased resistance to the cell wall-perturbing
Varol et al., 2018; Figure 3). Also, FKS2, encoding a β1,3-glucan compound SDS in cold-shock-stress-induced cells has also
synthase, is upregulated during heat stress, being its expression been attributed, at least partially, to the upregulation of DAN1
regulated by both CWI and Calcineurin pathways (Zhao et al., (Abe, 2007). The CWI pathway WSC1, BCK1, and SLT2 genes
1998; Figure 3). encoding a CWI sensor, the MAPKKK Bck1 and the MAPK
The ability to withstand elevated temperatures while Slt2, respectively, have also been implicated in response and
maintaining high growth rates and ethanol productivity can be adaptation to cold temperature-induced-stress, being Slt2
beneficial for bioethanol production and could alleviate some phosphorylation partially dependent on the Wsc1 CWI sensor
of the costs associated with the cooling of the bioreactors (Córcoles-Sáez et al., 2012; Figure 3). Psychrophilic yeasts,

yeasts adapted to low temperatures, with an optimal growth mannose backbone present in CWPs, and LDB7, encoding a
performance at 15◦ C, are studied due to its biotechnological component of the chromatin structure remodeling complex,
potential, in particular for the production of cold-active involved in the regulation of the mannosylphosphate content
enzymes (Buzzini et al., 2012). Interestingly, the absence of the of mannoproteins (Kubota et al., 2004; Auesukaree et al., 2009;
SWI4 or SWI6 genes, encoding transcriptional activators of Teixeira et al., 2009). Moreover, the CWP-encoding genes PIR3,
the CWI pathway in Metschnikowia australis W7-5, leads to SED1, SPI1, and YGP1, as well as the GPI-CWPs-encoding
impaired growth at temperatures as low as 5◦ C, suggesting that genes of the TIR family (TIR1-3 and TIP1), were found to
these genes are determinants of tolerance to low temperature in be transcriptionally responsive to ethanol stress (Ogawa et al.,
this species (Wei et al., 2021). 2000; Rossignol et al., 2003; Wu et al., 2006; Udom et al.,
2019; Figure 3). The overrepresentation of genes related to the
mannoprotein-rich outer layer of the cell wall in response to
Ethanol – and methanol – induced ethanol-induced stress suggests that mannoproteins have a role
stresses in yeast adaptation to this stress, limiting ethanol’s access to
the plasma membrane and thus counteracting ethanol-induced
Ethanol toxicity is arguably the major environmental stress membrane permeabilization and subsequent deleterious effects.
limiting industrial titres and overall productivity in a wide Due to its amphiphilic nature, ethanol can bind to the exposed
range of industrial yeast fermentations (Gibson et al., 2007; proteins at the outer layer of the cell wall, likely altering its
Parapouli et al., 2020). Accumulation of high concentrations organization and increasing cell wall porosity (Zlotnik et al.,
of ethanol, whether during bioethanol production, wine 1984; De Nobel et al., 1990; Udom et al., 2019).
and brewing industries, or other alcoholic fermentations, Genes related to chitin and glucan synthesis, namely CHS1
often results in decreased fermentation yield or complete (chitin), FKS1 (β1,3-glucans), ACF2 (β1,3-glucans), and KRE6
cessation of yeast metabolic activity and fermentation arrest (β1,6-glucans), as well as genes involved in cell wall integrity
(Walker and Basso, 2020). (PUN1) and cell wall organization (SIT4), were also found
Due to its liposolubility, ethanol disrupts plasma to be involved in ethanol tolerance (Kubota et al., 2004;
membrane lipid organization, increasing its fluidity, non- Auesukaree et al., 2009; Teixeira et al., 2009; Mota et al.,
specific permeability, and compromising transmembrane 2021). The upregulation of FKS1 and also of SED1 and
electrochemical potential (van Uden, 1985). Among the SMI1 genes, involved in cell wall biosynthesis depends on the
adaptive responses is the alteration of plasma membrane Znf1 transcription factor, recently implicated in adaptation
composition (e.g., increase in ergosterol content and in to ethanol stress (Samakkarn et al., 2021). Consistent with a
unsaturated/saturated fatty acid ratio) leading to increased transcriptional response involving multiple components of the
lipid order and counteracting plasma membrane fluidisation cell wall under ethanol stress, elements of the CWI signaling
(Navarro-Tapia et al., 2018), together with and adaptive pathway, namely the membrane sensors Mid2 and Wsc1, the
response at the level of the cell wall (Ding et al., 2009; Stanley MAPKKK Bck1, and the MAPK Slt2, were found to be crucial
et al., 2010). Remarkably, the impairment of plasma membrane for maximum tolerance to ethanol stress (Fujita et al., 2006;
integrity was shown to influence the nanomechanical properties Auesukaree et al., 2009; Teixeira et al., 2009). Also, yeasts
of the cell wall during ethanol stress (Schiavone et al., 2016) deficient in either one of the two Slt2-activated SBF subunits,
(Figure 3). Specifically, ethanol-induced changes to the Swi4 and Swi6, reveal higher sensitivity to ethanol (Udom
plasma membrane, compromising the proper delivery of et al., 2019). The SBF complex controls the expression of
plasma membrane-anchored GPI-CWPs to the membrane FKS2 and CRH1, coding for a β1,3-glucan synthase and a
via the secretory pathway, affect their crosslinking to cell chitin transglycosylase involved in glucan-chitin crosslinking,
wall polysaccharides resulting in reduced cell wall stiffness respectively; these genes were shown to be upregulated during
(Schiavone et al., 2016; Figure 3). ethanol stress (Udom et al., 2019; Figure 3). Additionally, the
Several chemogenomic studies have implicated genes related HOG pathway also seems to contribute to the regulation of
to cell wall biosynthesis, cell wall remodeling, and CWI pathway the transcriptional response of cell wall genes during ethanol
as determinants of ethanol tolerance (Kubota et al., 2004; Fujita stress, since the dysfunction of the HOG pathway leads to
et al., 2006; van Voorst et al., 2006; Auesukaree et al., 2009; decreased expression of FKS2 and CRH1 (Udom et al., 2019).
Teixeira et al., 2009). Additionally, suitable supplementation Furthermore, the wall of yeast cells exposed to ethanol exhibits
of the fermentation medium with potassium, zinc or inositol higher resistance to lyticase and zymolyase treatment (Udom
was shown to improve tolerance to ethanol stress (Krause et al., 2019). In summary, the mechanism underlying ethanol
et al., 2007; Zhao et al., 2009; Xu et al., 2020). Genes tolerance involves a collaborative role of the CWI and HOG
reported as determinants of ethanol tolerance include MNN10, signaling pathway in the transcriptional regulation of cell
MNN11, ANP1, and HOC1, encoding four subunits of the wall genes leading to cell wall changes (Udom et al., 2019;
polymerase complex responsible for the elongation of the Figure 3).

Not many non-conventional yeasts can compete with pathway for activation of methanol-inducible genes (Ohsawa
S. cerevisiae when it comes to ethanol production and tolerance, et al., 2017). Additionally, differences in methanol metabolism,
but some have other interesting features that could make their vector transformation efficiency, growth and heterologous
use in the bioethanol industry appealing. K. marxianus, known protein production between different K. phaffii strains were
for its thermotolerance and ability to metabolize several carbon related with cell wall integrity (Zhang et al., 2020), providing
sources (Thorwall et al., 2020), has a fair number of studies another example of the important role of cell wall.
dedicated to understanding the response to ethanol stress (Diniz
et al., 2017; Alvim et al., 2019; Mo et al., 2019; da Silveira
et al., 2020), although not much is known about ethanol- Low- or high-pH-induced stress
induced changes to its cell wall. However, the adaptive evolution
under ethanol stress was found to lead to the improvement Cell wall composition and architecture and the CWI
of multiple pathways, including cell wall biogenesis, suggesting pathway were also implicated in yeast adaptive response to
that cell wall remodeling is part of a strategy to mitigate acid and alkaline stress conditions (Claret et al., 2005; Serrano
the toxic effects of ethanol, also in this species (Mo et al., et al., 2006; De Lucena et al., 2012). However, the mechanisms
2019). The increase in cell wall thickness also occurs in underlying yeast response and tolerance to acidic conditions
Saccharomyces boulardii under ethanol stress (Ramírez-Cota are complex and dependent not only on the pH value but
et al., 2021). S. boulardii is known for its probiotic capacities also on the nature of the acid used to adjust low pH. Strong
as a biotherapeutic agent in infections and medical disorders inorganic acids, such as sulphuric acid and hydrochloric acid,
(Hudson et al., 2016; Suvarna et al., 2018; Hossain et al., 2020) are fully dissociated at any external pH, while weak organic
and is a promising species to be used in certain crafts of acids dissociation depends on medium pH and their pKa, the
beer fermentation (Ramírez-Cota et al., 2021). In Issatchenkia toxic form being the liposoluble non dissociated form (Carmelo
orientalis, with potential to be used in winemaking, cell wall- et al., 1996, 1997; Booth and Stratford, 2003). Since the plasma
related genes GAS4 (β-1,3-glucanosyltransferase involved in membrane of unstressed cells is very poorly permeable to H+ ,
glucan elongation), FLO1 (CWP involved in adhesion events the effect of strong acids relies, essentially, on the concentration
important for flocculation) and IFF6 (GPI-CWP involved in cell of H+ /medium pH (Carmelo et al., 1996, 1997; Lucena et al.,
wall organization) were found to be up-regulated under ethanol 2020). For this reason, pH stress and stress induced by organic
stress (Miao et al., 2018). acid stress at low pH are discussed separately.
A recent chemogenomic analysis reported that, in
S. cerevisiae, methanol and ethanol, share genetic determinants Acid pH-induced stress
of tolerance involved in cell wall maintenance (Mota et al., In bioethanol production, yeast biomass is reused after being
2021). Methanol is a feedstock alternative to sugar-based raw washed between successive batches using inorganic acids. It is a
substrates for biorefinery processes and a toxic compound common procedure, frequently carried out at a pH below 3.0
commonly found in crude glycerol, a by-product of the as a means of eliminating contaminant bacteria from pitching
biodiesel industry, and in hydrolysates from pectin-rich yeast. This disinfection treatment, together with the presence
biomass residues (Yasokawa et al., 2010; Martins et al., 2020; of toxic metabolites and other stressful conditions occurring
Mota et al., 2021). Methanol and ethanol tolerance genes include during fermentation, may lead to the loss of cell viability and
FKS1 and SMI1 (β1,3-glucan synthesis), ROT2 (β1,6-glucan limit fermentation yield (Simpson and Hammond, 1989; De
synthesis), MNN11 (mannosylation of CWPs), and WSC1 (CWI Melo et al., 2010; Lucena et al., 2020). A scalable and economic
pathway membrane sensor). However, KRE6, CWH41 (β1,6- solution to control bacterial contamination during alcoholic
glucan synthesis) and GAS1 (β1,3-glucan chain elongation fermentation is to run the fermentations at low pH (<4.0),
and branching) were found to be required for maximum at which growth and viability of most bacteria are drastically
tolerance to methanol but not for equivalent inhibitory reduced (Narayanan et al., 2016). Thus, understanding how
concentrations of ethanol (Mota et al., 2021). This suggests that, yeast strains tolerate low pH set up with strong acids may enable
despite the similarities of these alcohols, equivalent inhibitory the improvement of ethanol yield and reduce production costs
concentrations might impact the cell wall differently and, as (Brosnan et al., 2000). It is likely that during fermentation,
such, elicit not fully overlapping remodeling responses (Mota organic acids (weak acids) may also play a role since they are
et al., 2021). The CWI pathway is implicated in methanol produced during yeast metabolism and may be already present
adaptation in Komagataella phaffii (formerly Pichia pastoris), in the fermentation medium (e.g., when lignocellulosic biomass
involving the upregulation of the SLT2 homolog encoding gene hydrolysates are used).
in K. phaffii (Zhang et al., 2020). The homolog of Wsc1 and In response to acid pH, the cell wall structure and
Wsc3 CWI sensors in the methylotrophic yeast K. phaffii were composition suffers alteration (Cabib et al., 1989; Kapteyn
implicated in sensing methanol, interacting upstream with et al., 2001) leading to deformation of surface morphology
the K. phaffii homolog of Rom2, a GEF of S. cerevisiae CWI (De Lucena et al., 2015). Cell wall chitin levels decrease at

growth pH values below 5.0, likely as a result of increased cooperation between Slt2 and Crz1 for the expression of FKS2
chitinase activity (Cabib et al., 1989; Figure 3). Many of the in response to cell wall injury (De Lucena et al., 2012; Figure 3).
genes found to be upregulated at low pH are related to cell This Ca2+ -dependent response is likely responsible for the
wall biogenesis, including FKS1 (β1,3-glucan synthase), GAS1 increment of CWI protein trafficking and their localisation at
(β-1,3-glucanosyltransferase involved in cell wall remodeling- cell surface to repair the structural changes caused by medium
elongation of (1 → 3)-β-D-glucan chains and branching), acidification (Lucena et al., 2020). Together, CWI, HOG, and
CHS1 (chitin synthase), NCW2 (GPI-protein involved in chitin- calcineurin signaling pathways ensure the post-translational
glucan assembly), KRE6 (glucosyl hydrolase required for β1,6- activation of the transcription factors needed to promote cell
glucan synthesis) and MNN9 (mannosyltransferase subunit wall maintenance and regeneration to survive acidic pH stress.
involved in wall protein mannosylation) (De Melo et al., 2010;
De Lucena et al., 2012; Figure 3). Interestingly, using QTL Alkaline pH stress
mapping to uncover the genetic basis of a bioethanol industrial The yeast S. cerevisiae proliferates better at acidic than
strain Pedra-2 (PE-2) tolerance, a prevalent non-synonymous at neutral or alkaline pH and medium alkalinisation has
mutation (A631G) in GAS1 was identified during growth at widespread effects in yeast physiology (Serra-Cardona et al.,
low pH induced by sulfuric acid exposure, reinforcing the 2015). An increase of pH from 4.0 to 6.0 leads to the decrease of
idea of the relevant role of this GPI-protein in yeast tolerance the relative proportion of β1,6-glucans in the β-glucan fraction
in acidic environments (Coradini et al., 2021). Together with of the cell wall (Aguilar-Uscanga and François, 2003) and cells
the up-regulation of genes related with 1,3-β-glucan synthesis, grown at pH 6.0 are more susceptible to zymolyase treatment
elongation, and anchoring, low pH stress leads to increased cell (Aguilar-Uscanga and François, 2003; Figure 3). The CWI
wall resistance to compounds with β1,3-glucanase activity and pathway is necessary for tolerance to alkaline pH, as shown
to the establishment of more alkali-sensitive linkages between by the strong alkali-sensitive phenotype of the bck11, slt21,
CWPs and the β1,3-glucan network (Kapteyn et al., 2001; swi41, and swi61 mutants (Serrano et al., 2006). The alkaline
De Melo et al., 2010; De Lucena et al., 2012, 2015; Lucena stress-mediated activation of Slt2 was also shown to depend
et al., 2020). This suggests that low pH established by a strong on the CWI Wsc1 membrane sensor (Serrano et al., 2006;
inorganic acid affects the β-glucan fraction of the cell wall. Kwon et al., 2016; Figure 3). Both FKS2 and GAS1 encoded
As for other stresses, response to acid pH imposed by proteins, involved in the synthesis and elongation of β1,3-
inorganic acids involves a crosstalk between different signaling glucans respectively, are required to resist alkaline stress, and
pathways. The CWI signaling pathway is involved in response likely play a major role in altering the ratio between different
to low pH in S. cerevisiae and has been proposed as the main types of glucans in the cell wall (Serrano et al., 2006). The Ca2+ -
mechanism for tolerance to acid pH (Claret et al., 2005; De dependent calcineurin response has also been implicated in the
Lucena et al., 2012; Figure 3). Its activation is mainly mediated regulation of cell wall synthesis during alkaline stress by the
by Mid2, but also by Wsc1, with the latter appearing to have upregulation of FKS2 expression via the calcineurin-activated
a more prominent role in activating the general response of transcription factor Crz1 (Viladevall et al., 2004; Figure 3).
the cell to this stress (Claret et al., 2005; De Lucena et al., Changes in cell wall composition were also implicated
2012). The proposed model is that cell wall injury due to acid in Y. lipolytica adaptation to high pH stress (Sekova et al.,
stress results in lower turgor and consequently mimics the 2019). In particular, the structural mannoprotein YlPir1 is
effect of hyper-osmotic shock, justifying the activation of the abundant in the cell wall in unstressed conditions but absent
HOG pathway (De Lucena et al., 2012; Figure 3). The HOG when Y. lipolytica cells are exposed to high pH stress (Sekova
pathway then appears to have a dual role. First, Hog1 activates et al., 2019). This readjustment is consistent with the fact that
the protein complex Msn2/4, which induces the expression of mannans, unlike other main polysaccharides of the cell wall, are
ESR genes, including RGD1, a major regulator of yeast survival prone to alkaline hydrolysis, and therefore unstable at high pH
at low pH stress, that encodes a protein implicated in the (Sekova et al., 2019).
activation of CWI pathway under acid stress (Claret et al., To summarize, there are major differences between the
2005). Second, the Hog1 kinase may help to establish a positive signaling responses elicited by acidic and alkaline pH stresses
feedback loop at the downstream module of the CWI pathway involving the cell wall. First, Mid2 appears to be the main sensor
by cooperating with the Slt2-activated Rlm1 transcription factor activating the CWI pathway in response to acidic pH, while
to increase the expression of SLT2 (Claret et al., 2005; De Wsc1 is the main sensor in alkaline pH (Claret et al., 2005; Fuchs
Lucena et al., 2012). Therefore, the HOG pathway can activate and Mylonakis, 2009; Serra-Cardona et al., 2015). Second, acidic
the CWI pathway while bypassing its membrane sensors. pH stress mostly leads to the transcription of Rlm1-dependent
The Ca2+ /calmodulin-dependent calcineurin pathway is also genes, while alkaline pH stress favors transcription of SBF-
involved in the response to acid pH, and interacts with the CWI dependent genes. Third, while the CWI pathway manages acidic
pathway by activating Cch1/Mid1 calcium channels by Slt2, stress in a Hog1-dependent manner, response to alkaline stress
the Crz1 transcription factor by Rho1-Skn7, and through the is Hog1-independent (Fuchs and Mylonakis, 2009).

Organic acid-induced stress yeast cell population to sudden exposure to a sub-lethal stress
induced by acetic acid (Ribeiro et al., 2021). Yeast cell wall
The response and tolerance of the yeast cell to the various resistance to lyticase activity was found to increase during
industrially relevant weak acids and the underlying toxicity acetic acid-induced growth latency, corresponding to the period
mechanisms are not fully shared by all the acids, with specific of yeast population adaptation to sudden exposure to acetic
mechanisms for a weak acid/group of weak acids (Mira et al., acid. This response was correlated with the increase of cell
2010c). In general, and broadly speaking, the higher the stiffness, assessed by atomic force microscopy (Ribeiro et al.,
lipophilicity of each of a weak acid is, the higher its toxicity. 2021; Figure 3). The increased content of cell wall β-glucans,
The straight medium chain weak acids (e.g., butyric, hexanoic, also assessed by fluorescence microscopy, and the slight increase
octanoic, and decanoic acids) and sorbic and benzoic acids are of the transcription level of the GAS1 gene encoding a β-1,3-
more lipophilic and toxic than the short-chain volatile fatty acids glucanosyltransferase that leads to elongation of β1,3-glucan
(VFA) formic, acetic, and propionic acids (Mira et al., 2010c; chains, were also implicated (Ribeiro et al., 2021; Figure 3).
Skoneczny, 2018). These observations reinforce the notion that the adaptive yeast
response to acetic acid stress involves a coordinate alteration of
Acetic acid stress the cell wall at the biophysical and molecular levels, essential to
Acetic acid is widely used as a food preservative in the limit the futile cycle associated to the re-entry of the toxic acid
food industry and is also a major inhibitory compound present form after the active expulsion of acetate from the cell interior
in lignocellulosic biomass hydrolysates limiting the use of this (Ribeiro et al., 2021).
low cost and abundant biomass (Palma et al., 2018; Cunha The adaptive genomic response to acetic acid in S. cerevisiae
et al., 2019). Acetic acid is also produced by yeast metabolic is mainly regulated by the Haa1 transcription factor involved
activity and can lead, together with ethanol and other yeast toxic in the direct, or indirect, transcriptional activation of
metabolites, to decreased ethanol yield and even fermentation approximately 80% of acetic acid-responsive genes and
arrest depending on the level of stress (Palma et al., 2018; likely involved in the response at the cell wall level (Mira
Cunha et al., 2019; Palma and Sá-Correia, 2019). Elucidation et al., 2010a, 2011). Haa1 increased expression or Haa1 specific
of the mechanisms underlying yeast adaptation and tolerance mutations lead to increased tolerance to acetic acid stress
to acetic acid is instrumental to pave way for strain and and to a lower intracellular accumulation of acetate (Tanaka
process optimisation in several important biotechnological and et al., 2012; Palma et al., 2018). Overexpression of HAA1
food industries. improves cell wall robustness in response to this weak acid,
When the external pH is below acetic acid pKa (below as suggested by the decreased susceptibility of the cell wall to
4.75 at 25◦ C) (Lide, 2003), the undissociated form of the lyticase activity mediated disruption (Cunha et al., 2018). Also,
acid (CH3 COOH) is able to passively diffuse through the YGP1 and SPI1, encoding CWPs, belong to the Haa1 regulon;
plasma membrane lipid bilayer (Casal et al., 1996; Mira et al., they are upregulated under acetic acid stress and contribute
2010c; Palma et al., 2018; Palma and Sá-Correia, 2019). Once to yeast tolerance (Simões et al., 2006; Sakihama et al., 2015;
in the near-neutral cytosol, acetic acid dissociates into the Figure 3). Increased mRNA levels from YGP1 were reported in
negatively charged acetate counterion, CH3 COO− , releasing cells overexpressing HAA1 (Tanaka et al., 2012). These results
protons, H+ . Being unable to cross the hydrophobic lipid suggest that not only the activation of acetate expulsion through
layer due to the electric charge, these ions accumulate in the efflux pumps is involved in acetic acid tolerance, as proposed
cytosol, resulting in decreased intracellular pH, increased turgor (Piper et al., 1998; Holyoak et al., 1999; Tenreiro et al., 2002;
pressure and oxidative stress, disrupting normal metabolism Fernandes et al., 2005; Kawahata et al., 2006; Mira et al., 2010b),
(Mira et al., 2010c; Palma et al., 2018; Palma and Sá-Correia, but a more efficient restriction of the diffusional entry of acetic
2019; Ribeiro et al., 2022). acid, partially dependent of the CWP Ygp1, can also be involved
Several genome-wide studies have sought to shed light into (Tanaka et al., 2012). The Znf1 transcription factor was also
the global mechanisms involved in the response and tolerance implicated in acetic acid tolerance and in the upregulation of
of S. cerevisiae to acetic acid (Kawahata et al., 2006; Abbott et al., the YGP1 gene (Songdech et al., 2020).
2007; Almeida et al., 2009; Mira et al., 2010a,b; Bajwa et al., Genes involved in CWP mannosylation (MNN2, MNN9,
2013; Longo et al., 2015). Increased cell wall impermeabilization MNN11, KTR4), chitin synthesis (CHS1, CHS5), β1,3-glucan
in adapted yeast cells can reduce the passive diffusion of the synthesis (FKS1, ROM2), and β1,6-glucan synthesis (KRE6)
weak acids into the cytosol, in this way restraining the futile were also reported as being required for maximum tolerance
cycle associated with the re-entry of the liposoluble acid form of S. cerevisiae to acetic acid stress (Mollapour et al., 2009;
after the active expulsion of its counter-ion from the cell interior Mira et al., 2010b). However, the mRNA levels from RLM1,
(Ullah et al., 2013). Recently, it was reported a coordinate encoding a major transcriptional regulator of the CWI pathway,
and comprehensive view on the time course of the alterations and from Rlm1-target genes, were found to decrease in cells
occurring at the level of the cell wall during adaptation of a exposed to acetic acid stress, suggesting that the CWI pathway

is not the major key player in acetic acid stress response response to lactic acid stress (Kawahata et al., 2006; Figure 3).
(Ribeiro et al., 2021). Genes encoding elements of the MAPK module of the CWI
Zygosaccharomyces bailii is a common food spoilage yeast pathway (BCK1, SLT2), as well as genes involved in glucan
capable of adapting and proliferating in the presence of synthesis (KRE1, KRE11) and remodeling (GAS1), have also
remarkably high concentrations of acetic acid (Palma et al., been implicated in lactic acid tolerance (Kawahata et al., 2006;
2018). During exposure to acetic acid, several genes involved Suzuki et al., 2012).
in the modulation of plasma membrane composition and cell The Haa1 transcription factor also plays an important role
wall architecture were found to be differentially expressed in tolerance to lactic acid and is involved in the control of the
(Antunes et al., 2018). Among those genes is the homologue expression of CWPs (Abbott et al., 2008; Mira et al., 2010c;
of S. cerevisiae YGP1, encoding a cell wall-related glycoprotein, Sugiyama et al., 2014). As found for acetic acid stress (Kim
whose upregulation in the presence of acetic acid was shown to et al., 2019), exposure to lactic acid leads to Haa1 translocation
depend on ZbHaa1 (Palma et al., 2017; Antunes et al., 2018), from the cytoplasm to the nucleus where gene transcription, in
showing a high degree of similarity between the responses particular of YGP1 and SPI1 occurs (Sugiyama et al., 2014). The
involving the cell wall in both yeast species. In a K. marxianus overexpression of these two genes, encoding CWP, likely confers
strain isolated from agave, lyticase assays showed that the a stronger protective effect against lactic acid-induced toxicity
addition of KCl/KOH leads to the increase of cell wall robustness (Sugiyama et al., 2014).
in cells grown in the presence of acetic acid (Castillo-Plata et al., Due to the high tolerance of Zygosaccharomyces parabailii
2021). However, further studies are necessary to elucidate the to high lactic acid concentrations at low pH, this species was
link between changes in cell wall during acetic acid adaptation proposed as a promising novel host for lactic acid production
and potassium homeostasis (Castillo-Plata et al., 2021). In (Ortiz-Merino et al., 2018). In Z. parabailii, several cell wall-
I. orientalis, the expression of MPG1 gene, coding for a GDP- related genes were found to be down-regulated in the presence
mannose pyrophosphorylase involved in cell wall synthesis, of lactic acid (Ortiz-Merino et al., 2018). Under the stress
was also found to be upregulated under acetic acid stress conditions tested, during exponential growth in the presence
(Li et al., 2021). of lactic acid, a slight decrease in glucans was reported in
S. cerevisiae and Z. bailii, and a slight decrease in mannans in
Lactic acid stress S. cerevisiae (Berterame et al., 2016; Kuanyshev et al., 2016).
Lactic acid is another important weak acid in the food
industry and also in the pharmaceutical and cosmetic industries. Other weak acids
Its industrial production is currently carried out by lactic Propionic acid is commonly used to preserve baked goods
acid bacteria (Van Maris et al., 2004; Sauer et al., 2010) but and dairy (Suhr and Nielsen, 2004). Transcriptomic and
bacteria are sensitive to low pH, requiring large amounts chemogenomic studies have hinted at a role for the cell wall in
of neutralizing agents to counteract the acidification of the yeast adaptation to this weak acid (Fernandes et al., 2005; Mira
fermentation media, thus compromising the recovery yield et al., 2009). Specifically, CWP1 (encoding a GPI-CWP), BAG7
of precipitated lactic acid (Altaf et al., 2007; Yen et al., (β1,3-glucan synthesis), and KNH1 (β1,6-glucan synthesis) are
2010). Yeasts typically fare better than bacteria in acidic required to resist propionic acid stress, all of which are regulated
environments, which has motivated attempts to produce by the transcription factor Rim101 (Mira et al., 2009), suggesting
lactic acid through the heterologous expression of lactate that cell wall remodeling during adaptation to propionic acid
dehydrogenases in yeast (Dequin and Barre, 1994; Porro stress may be dependent on RIM101 expression.
et al., 1999; Pacheco et al., 2012). The success of such Sorbic and benzoic acids are two other weak acids used to
strategy and its industrial application require knowledge of preserve foods and beverages. In both cases, the S. cerevisiae
the mechanisms behind yeast tolerance to lactic acid stress. cell wall has been implicated in stress tolerance (De Nobel
Exposure to lactic acid leads to a decrease in cell wall et al., 2001; Simões et al., 2006). Common to the responses
glucan content and, to a lesser extent, of the mannan to sorbic and benzoic acids is the induction of SPI1, a GPI-
content of S. cerevisiae cell wall (Berterame et al., 2016; CWP that likely leads to the decrease of cell wall porosity and,
Figure 3). Several genes involved in the synthesis of cell in turn, limits the access to plasma membrane, thus reducing
wall polysaccharides, cell wall remodeling, and synthesis of membrane damage, intracellular acidification, and viability loss
mannoproteins are transcriptionally responsive and/or are (De Nobel et al., 2001; Simões et al., 2006; Figure 3). As
determinants of tolerance to lactic acid stress (Kawahata et al., previously mentioned, SPI1 is also activated in response to other
2006; Abbott et al., 2007; Suzuki et al., 2012). Specifically, weak acids and ethanol stress (Ogawa et al., 2000; Simões et al.,
genes required for glucan remodeling (EXG1, GAS2, SCW10), 2006; Wu et al., 2006).
cross-linking between β-glucans and chitin (CRH1), chitin Formic acid in an inhibitory weak acid present
synthesis (CHS1), and genes encoding mannoproteins required in lignocellulosic hydrolysates negatively impacting
for cell wall stability (HSP150, PIR3, SED1), are up-regulated in lignocellulosic-based biorefining (Cunha et al., 2019).

Under formic acid stress, S. cerevisiae cells exhibited a the important role of CWP in decreasing cell surface porosity
deformed shape, with collapsed cell wall edges, indicating that and increasing cell wall stability when coping with stress. The
the cell wall was damaged, and an FTIR analysis suggested that upregulation of genes involved in β1,3-glucan synthesis was also
chitin structure was altered (Zeng et al., 2022). S. cerevisiae reported to be shared by several stresses (heat, ethanol, low
genes involved in β1,3-glucan synthesis (FKS1, ELO2), β1,6- and high pH and formic acid stress) and during hyper-osmotic
glucan synthesis (TRS65), chitin synthesis (CHS5), CWP stress in Z. rouxii (Zhao et al., 1998; Viladevall et al., 2004; De
mannosylation (PMT2), cell wall integrity (PUN1), and CWI Melo et al., 2010; De Lucena et al., 2012; Udom et al., 2019;
pathway regulation (ROM2) are important determinants of Guo et al., 2020; Samakkarn et al., 2021; Zeng et al., 2022).
formic acid tolerance while FKS3, encoding an FKS1-2 homolog, Genes involved in β1,3-glucan elongation and branching were
is upregulated in response to this acid stress (Henriques et al., also found to be upregulated in response to low pH, acetic
2017; Zeng et al., 2022; Figure 3). Moreover, the upregulation and lactic acids-induced stresses and under ethanol stress in
of EXG2 encoding a major exoglucanase, and PKC1, encoding a I. orientalis (Kawahata et al., 2006; De Melo et al., 2010; De
CWI pathway kinase, was reported in an industrial S. cerevisiae Lucena et al., 2012; Miao et al., 2018; Ribeiro et al., 2021).
strain (S6), engineered to ferment xylose, when grown in a Genes involved in chitin synthesis found to be upregulated
medium with glucose and xylose supplemented with formic acid were also found to be shared by the response to low pH and
(Li et al., 2020). lactic acid stress in S. cerevisiae, and to hyper-osmotic stress in
Z. rouxii (Kawahata et al., 2006; De Melo et al., 2010; De Lucena
et al., 2012; Guo et al., 2020). Genes involved in β-glucan-chitin
Adaptive responses to several crosslinking were also found to be upregulated under ethanol
industrially relevant stresses involving and lactic acid stresses in S. cerevisiae, and under hyper-osmotic
the cell wall stress in Z. rouxii (Kawahata et al., 2006; Udom et al., 2019;
Guo et al., 2020). The upregulation of genes involved in β1,6-
Some of the responses involving the modification cell glucan synthesis are shared by oxidative and low pH stress
wall metabolism and cell wall physicochemical properties in in S. cerevisiae, and by hyper-osmotic stress in Z. rouxii and
yeasts are shared by relevant industrial stresses (Figure 3). For Z. mellis (De Melo et al., 2010; De Lucena et al., 2012; Sha
example, the CWI pathway is implicated in oxidative-, osmotic-, et al., 2013; Guo et al., 2020; Liu et al., 2021). Genes involved in
heat and cold-, ethanol- and low and high pH- induced stresses CWI pathway were found to be upregulated in oxidative-, heat-
(Kamada et al., 1995; Hohmann, 2002a; Claret et al., 2005; and low pH-induced stress in S. cerevisiae, under hyper-osmotic
García-Rodríguez et al., 2005; Mensonides et al., 2005; Vilella stress in Z. mellis, and under methanol stress in K. phaffii (Claret
et al., 2005; Fujita et al., 2006; Serrano et al., 2006; Auesukaree et al., 2005; De Lucena et al., 2012; Sha et al., 2013; Varol et al.,
et al., 2009; Teixeira et al., 2009; Córcoles-Sáez et al., 2012; 2018; Zhang et al., 2020; Liu et al., 2021). Genes involved in CWP
De Lucena et al., 2012; Pillet et al., 2014; Kwon et al., 2016; mannosylation were found to be upregulated in S. cerevisiae
Udom et al., 2019; Vaz et al., 2020). Also, the coordinated under low pH stress and in D. hansenii under hyper-osmotic
regulation involving the CWI and the HOG pathways occurs stress (Thomé, 2007; Gonzalez et al., 2009b; De Melo et al.,
during osmotic, heat, ethanol and low pH stresses (Kamada 2010; De Lucena et al., 2012). Genes involved in β1,3-glucan
et al., 1995; Hohmann, 2002a; García-Rodríguez et al., 2005; hydrolysis were found to be upregulated under lactic acid stress
Mensonides et al., 2005; De Lucena et al., 2012; Dunayevich in S. cerevisiae (Kawahata et al., 2006).
et al., 2018; Udom et al., 2019; Vaz et al., 2020) and the Of all the industrially relevant stresses herein described,
Calcineurin pathway interacts with the CWI pathway during exposure to several stresses were found to decrease, at least,
high and low pH stresses (Viladevall et al., 2004; De Lucena one type of cell wall polysaccharide in S. cerevisiae. Specifically,
et al., 2012). The reported upregulation of genes encoding CWPs a decrease in the β-glucan content was reported for heat-
was also observed under several stress induced conditions (e.g., (β1,3-glucans), high pH- (β1,6-glucans), lactic acid- (β1,3 and
under ethanol stress in S. cerevisiae and I. orientalis and under β1,6-glucans) induced stresses, and a decrease in mannans
acetic acid stress in S. cerevisiae and Z. bailii (Ogawa et al., was reported during lactic acid stress (Aguilar-Uscanga and
2000; Rossignol et al., 2003; Simões et al., 2006; Wu et al., 2006; François, 2003; Schiavone et al., 2014; Berterame et al., 2016).
Sakihama et al., 2015; Palma et al., 2017; Antunes et al., 2018; A slight decrease in the β-glucan content (β1,3 and β1,6-
Miao et al., 2018; Udom et al., 2019) and under oxidative, high glucans) was also reported for Z. bailii during lactic acid stress
and low temperature, low pH, lactic, sorbic and benzoic acids- (Kuanyshev et al., 2016). A decrease in the chitin content was
induced stresses in S. cerevisiae) (Abramova et al., 2001; Causton reported for inorganic acid-induced low pH in S. cerevisiae
et al., 2001; De Nobel et al., 2001; Sahara et al., 2002; Homma (Cabib et al., 1989). Nevertheless, an increase of cell wall
et al., 2003; Schade et al., 2004; Murata et al., 2006; Simões polysaccharide content was also reported, in particular an
et al., 2006; Abe, 2007; Sha et al., 2013; Sugiyama et al., 2014; increase in chitin and β1,6-glucans under heat stress and an
Varol et al., 2018). This common response is consistent with increase in the β-glucans content under acetic acid stress in

S. cerevisiae (Schiavone et al., 2014; Ribeiro et al., 2021). It is (Kawahata et al., 2006; Mira et al., 2010b). The increased
noteworthy to take in consideration that the methods used for expression of the HAA1 gene, encoding a transcription factor
cell wall polysaccharides quantification were not the same in and a major determinant of acetic acid tolerance in S. cerevisiae,
different articles and both the levels of stress and the adaptation led to the improvement of cell wall robustness under acetic
phase of the cells examined (early response, cells adapted to the acid stress, as suggested by the decreased susceptibility of the
stress) could be different or not clearly reported. cell wall to lyticase activity mediated disruption (Cunha et al.,
2018). Through Haa1 amino acid sequence engineering, a single
amino acid exchange at position 135 (serine to phenylalanine)
was found to lead to the upregulation of genes of the Haa1-
Improvement of yeast tolerance to regulon, increasing acetic acid tolerance, in particular YGP1
multiple stresses involving cell wall (Swinnen et al., 2017). The deletion of ATG22, encoding a
engineering vacuolar membrane protein that mediates the efflux of amino
acids resulting from autophagic protein degradation, was found
A few successful examples of the alteration of the to delay programmed cell death (PDC) induced by acetic acid.
physicochemical properties of the cell wall either by the genetic The deletion of ATG22 contributes to the maintenance of cell
engineering of the yeast cell or by the adaptive laboratory wall integrity, by preventing the decrease in total cell wall
evolution (ALE) of yeast cells leading to the increase of tolerance polysaccharides induced by PDC caused by severe acetic acid
to stress(es) have been reported in the literature. stress, increasing the transcript levels of CWI pathway genes
As referred above, through chemogenomic analyses, it was (Yang et al., 2006; Hu et al., 2019). This suggested ATG22 as
demonstrated that the expression of genes related with chitin a potential target for genetic engineering strategies to improve
and glucan synthesis, namely CHS1 (chitin), FKS1 and ACF2 yeast cell wall robustness and tolerance to acetic acid and other
(β1,3-glucans), KRE6 (β1,6-glucans), and others involved in industrial stresses. Enhanced tolerance to both acetic and formic
cell wall integrity (PUN1) and cell wall organization (SIT4), acids at low pH (pH 2.4 or below) by expressing the GAS1 gene
are required for maximum tolerance to ethanol in S. cerevisiae of Issatchenkia orientalis in S. cerevisiae was reported (Wada
(Kubota et al., 2004; Auesukaree et al., 2009; Teixeira et al., et al., 2020). Also, the overexpression of GAS1 in S. cerevisiae
2009; Mota et al., 2021). Superior fermentation performance led to increased lactic acid productivity at low pH (Zhong et al.,
of lignocellulosic hydrolysates was reported for a recombinant 2021), reinforcing the importance of GAS1, encoding a beta-1,3-
S. cerevisiae WXY70 strain overexpressing the CCW12 gene, glucanosyltransferase, in this context (Baek et al., 2017).
encoding a cell wall mannoprotein, compared to the control As previously referred, chemogenomic studies
strain, and CCW12 expression was found to improve cell demonstrated that genes related with cell wall polysaccharide
wall stability and tolerance to the growth inhibitors present synthesis (FKS1, KRE6) and cell wall mannosylation (MNN10,
(Kong et al., 2021). The deletion of GAL6, encoding a cysteine ANP1) are determinants of tolerance to osmotic stress (high
aminopeptidase with homocysteine-thiolactonase activity, was glucose concentrations) in S. cerevisiae (Ando et al., 2006;
found to lead to improved growth and higher viability of Teixeira et al., 2010). In Pichia pastoris (now Komagataella
S. cerevisiae, in the presence of ethanol stress (Yazawa et al., phaffii), the deletion of YPS7, encoding a putative GPI-linked
2007). The gal61 cells showed increased resistance to zymolyase aspartyl protease, led to increased osmotic tolerance and this
activity indicating the occurrence of structural changes in the gene was proposed as a promising molecular target for the
cell wall (Yazawa et al., 2007). A marked increased tolerance to engineering of yeast robustness (Guan et al., 2012). This species
ethanol stress associated with transcription rewiring involving is used to produce heterologous proteins in the pharmaceutical
cell wall synthesis was also identified in the highly–ethanol and food industry.
tolerant strain K. marxianus FIM1 obtained by ALE in an In a laboratory adaptively evolved K. marxianus strain
ethanol supplemented medium (Mo et al., 2019). Among exhibiting a significantly improved tolerance to high
the identified changes at the transcriptional level were the temperatures, a single nucleotide polymorphism was found in
alterations related with the upregulation of cell wall metabolism the coding region of the exoglucanase gene EXGI, required for
involving, in particular, chitin synthesis (CHS3), β1,6-glucan cell wall remodeling (Ai et al., 2022).
synthesis (KNH1), glucanosyltransferases activity involved in
β1,3-glucan branching and elongation (GAS4) and the cell wall
integrity pathway (BCK1, MID2, WSC3) (Mo et al., 2019). Concluding remarks
Numerous genes encoding proteins required for cell
wall polysaccharides synthesis (FKS1, ROM2, KRE6, CHS1, The important role played by the cell wall in the adaptation
CHS5), cell wall remodeling (GAS1) and protein mannosylation and tolerance of yeasts to different stresses of biotechnological
(MNN2, MNN9, MNN11, KTR4) were found to be determinants interest emerges from this review article. Although several
of acetic acid stress tolerance by chemogenomic analyses evidences support this idea, the truth is that these evidences

largely come from genome-wide analyses of the response Author contributions

of yeasts to various stresses. Furthermore, the experimental
conditions and levels of stress used are in general different IS-C, RR, and NB-M conceived and designed the study.
and only part of the studies involves a time-course analysis RR and NB-M performed the literature search, prepared the
covering the various stages of adaptation and growth under figures, and wrote the first manuscript draft. IS-C and RR
stress. Therefore, it is likely that the apparent divergences completed and revised the manuscript drafts. All authors
reported are due to this fact. approved the final manuscript.
This review article also provides information on how
the different signaling pathways coordinate to elicit changes
at the level of the yeast cell wall in response to different
relevant stresses. However, it is important to highlight
Funding
that, in industrial bioprocesses, several stresses are often
Work in the laboratory of IS-C was supported by
present simultaneously, which further complicates the goal of
‘Fundação para a Ciência e a Tecnologia’ (FCT) projects:
providing a comprehensive description of what happens during
PTDC/BBB-BEP/0385/2014, ERA-IB-2/0003/2015, PTDC/FIS-
adaptation to adverse process conditions. It is noteworthy
NAN/6101/2014; and Ph.D. fellowships to RR (FCT-
to take in consideration that yeast cells exposed to mild
Ph.D. Programme AEM—Applied and Environmental
stress develop tolerance not only to higher doses of the
Microbiology; PD/BD/135204/2017) and NB-M (FCT Ph.D.
same stress, but also to stress caused by other agents. This
Programme BIOTECnico-Biotechnology and Biosciences;
phenomenon, known as cross-protection, is based on the
PD/BD/150339/2019). Funding received from FCT by iBB—
existence of integrating mechanisms that senses and responds
Institute for Bioengineering and Biosciences (UIDB/04565/2020
to different forms of stress (Estruch, 2000). Concerning the
and UIDP/04565/2020) and by i4HB (LA/P/0140/2020), is
cell wall, the physiological observations reported and the
also acknowledged.
integrated molecular responses here described provide the
basis for the involvement of this dynamic organelle in cross-
stress protection.
Most of the review paper is dedicated to the model Conflict of interest
yeast and cell factory Saccharomyces cerevisiae. However, the
scarce available information in the literature concerning non- The authors declare that the research was conducted in the
conventional yeast species of biotechnological relevance is absence of any commercial or financial relationships that could
also mentioned throughout the text. A deeper understanding be construed as a potential conflict of interest.
of the nature of the molecular response and the changes
occurring at the cell envelope level would be valuable and
allow the development of more rational strategies to construct Publisher’s note
superior yeasts for biotechnology and to control the activity of
food spoiling yeasts. Genome-wide analyses are contributing All claims expressed in this article are solely those of the
to identify a wealth of cell wall-related promising targets authors and do not necessarily represent those of their affiliated
for the improvement of yeast tolerance. However, more in organizations, or those of the publisher, the editors and the
depth molecular and cellular studies are instrumental to better reviewers. Any product that may be evaluated in this article, or
understand the somewhat overlooked role of the cell wall in claim that may be made by its manufacturer, is not guaranteed
tolerance to multiple stresses in yeasts. or endorsed by the publisher.
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Yeast Cell Wall and Tolerance To Stress

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PUBLISHED 28 July 2022

The cell wall and the response

cell wall, yeasts of biotechnological relevance, stress response, stress tolerance,

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Introduction course of industrial bioprocesses (Klis, 2002; Stewart, 2017).

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largely come from genome-wide analyses of the response Author contributions

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