Cited by 266Fungal and yeast genetics researchAntifungal resistance and susceptibilityBacterial Genetics and Biotechnology

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Our Paths Might Cross: the Role of the Fungal Cell Wall Integrity Pathway in Stress Response and Cross Talk with Other Stress Response Pathways

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Fuchs, Beth Burgwyn, Mylonakis, Eleftherios·2009·Eukaryotic Cell

DOI 10.1128/ec.00193-09PMC PMC2772411

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Abstract

Fungi occupy diverse environments and are subjected to many extreme conditions. Among the stressful conditions faced by fungi are pH changes, osmotic changes, thermal changes, oxide radicals, nutrient deprivation, and exposure to chemicals. These adversities can be found either in the environment or in animal and human hosts. The cell wall integrity (CWI) pathway provides a means to fortify and repair damages to the cell wall in order to withstand stressful environments. The CWI pathway in comprised of cell wall stress sensors that lead to activation of a mitogen-activated protein kinase (MAPK) cascade. Signaling through the MAPK cascade leads to expression of transcription factors that facilitate biosynthesis of cell wall components and actin organization. Given the relatively limited number of components of the CWI pathway and the very diverse stimuli, there must be a means of expanding the pathway. To manage the diverse stress conditions, the CWI pathway cross talks with other pathways or proteins, and these cross talk events enhance the signaling capabilities of the CWI pathway. Lateral influences that facilitate maintaining the cell wall under stress conditions are TOR signaling, calcineurin signaling, the high-osmolarity glycerol pathway, the cyclic AMP-protein kinase A pathway, and additional proteins. In this article, we highlight several of the cross talk events that have been described for Saccharomyces cerevisiae and several other fungi.

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BackgroundInfluential
Signaling Alkaline pH Stress in the Yeast Saccharomyces cerevisiae through the Wsc1 Cell Surface Sensor and the Slt2 MAPK Pathway
Serrano, R., Martı́n, H., Casamayor, A., & Ariño, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604497200 · Cited by 129 · cited 4×
“This is exemplified by alkaline tolerance for a wsc1 mutant strain that contains a bck1-20 allele to induce constitutive activation of Slt2/Mpk1 (68).”
BackgroundInfluential
Fission yeast Tor1 functions in response to various stresses including nitrogen starvation, high osmolarity, and high temperature
Available, N. A. N., Available, N. A. N., Available, N. A. N., Available, N. A. N., Available, N. A. N., Available, N. A. N., & Available, N. A. N. (2001) · Current Genetics · doi:10.1007/s002940100198 · Cited by 128 · cited 3×
“pombe, each encoding two Tor proteins, Tor1 and Tor2 (30, 37).”
Background
Regulation of the Saccharomyces cerevisiae Slt2 Kinase Pathway by the Stress-inducible Sdp1 Dual Specificity Phosphatase
Hahn, J., & Thiele, D. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202557200 · Cited by 126 · cited 2×
“Slt2/Mpk1 is negatively regulated by Msn2/Msn4-dependent Sdp1 from the cAMP-PKA pathway by direct dephosphorylation of Slt2/Mpk1 under heat shock conditions (28).”
Background
The Saccharomyces cerevisiae sln1p-ssk1p two-component system mediates response to oxidative stress and in an oxidant-specific fashion
Singh, K. K. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00432-9 · Cited by 119 · cited 1×
“A key defense against oxidative stress is the HOG pathway (1, 2, 69).”
Background
Spm1, a stress‐activated MAP kinase that regulates morphogenesis in S.pombe
Zaitsevskaya-Carter, T., & Cooper, J. A. (1997) · The EMBO Journal · doi:10.1093/emboj/16.6.1318 · Cited by 117 · cited 3×
“S. pombe poses an exception where the CWI pathway component Slt2/Mpk1 homolog Pmk1 (72, 83) (Table 1) is activated regardless of whether the osmotic stressor is hyperosmotic or hypoosmotic (51).”
BackgroundInfluential
The calmodulin‐dependent protein phosphatase catalytic subunit (calcineurin A) is an essential gene in Aspergillus nidulans.
Rasmussen, C. D., Garen, C. R., Brining, S. K., Kincaid, R. L., Means, R. L., & Means, A. R. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06544.x · Cited by 115 · cited 1×
“neoformans (57), and Aspergillus nidulans (64).”
Stress-induced Response, Localization, and Regulation of the Pmk1 Cell Integrity Pathway in Schizosaccharomyces pombe
Madrid, M., Soto, T., Khong, H.-K., Franco, A., Vicente‐Soler, J., Pérez, P., Gacto, M., & Cansado, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506467200 · Cited by 115
PKC1 Is Essential for Protection against both Oxidative and Nitrosative Stresses, Cell Integrity, and Normal Manifestation of Virulence Factors in the Pathogenic Fungus Cryptococcus neoformans
Gerik, K. J., Bhimireddy, S. R., Ryerse, J. S., Specht, C. A., & Lodge, J. K. (2008) · Eukaryotic Cell · doi:10.1128/ec.00146-08 · Cited by 107 · cited 5×
“Those authors suggest that an alternative pathway extends from Pkc1 to provide for protection against oxidative stress (26).”
BackgroundInfluential
The Pbs2 MAP kinase kinase is essential for the oxidative-stress response in the fungal pathogen Candida albicans
Arana, D. M., Nombela, C., Alonso‐Monge, R., & Plá, J. (2005) · Microbiology · doi:10.1099/mic.0.27723-0 · Cited by 104 · cited 2×
“The phosphorylation of Mkc1 is also Pbs2 and Hog1 dependent, indicating a cross talk event between the CWI and HOG pathways in response to oxide stress (2).”
Background
cDNA cloning of a calcineurin B homolog in Saccharomyces cerevisiae
Kuno, T., Tanaka, H., Mukai, H., Chang, C., Hiraga, K., Miyakawa, T., & Tanaka, C. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)81188-x · Cited by 94 · cited 2×
“S. cerevisiae carries two redundant calcineurin A genes, CNA1 and CNA2 (12, 49), and a single copy of the calcineurin B gene, CNB1 (13, 42).”
Background
Stress-specific Activation Mechanisms for the “Cell Integrity” MAPK Pathway
Harrison, J. C., Zyla, T. R., Bardes, E. S. G., & Lew, D. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306110200 · Cited by 92 · cited 3×
“Interestingly, the activation of Slt2/Mpk1 by heat shock is Pkc1 and Bck1 independent (29).”
BackgroundMethod
The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth
Eng, W.-K., Faucette, L. F., McLaughlin, M. M., Cafferkey, R., Koltin, Y., Morris, R. A., Young, P. R., Johnson, R. K., & Livi, G. P. (1994) · Gene · doi:10.1016/0378-1119(94)90633-5 · Cited by 86 · cited 1×
“cerevisiae leads to increased sensitivity to the calcineurin inhibitor cyclosporine (20), suggesting an interplay between the CWI pathway and calcineurin.”
Background
IRA2 , a Second Gene of Saccharomyces cerevisiae That Encodes a Protein with a Domain Homologous to Mammalian ras GTPase-Activating Protein
Tanaka, K., Nakafuku, M., Tamanoi, F., Kaziro, Y., Matsumoto, K., & Toh‐e, A. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.8.4303-4313.1990 · Cited by 85
Regulatory Subunit (CNB1 Gene Product) of Yeast Ca2+/Calmodulin-Dependent Phosphoprotein Phosphatases Is Required for Adaptation to Pheromone
Cyert, M., & Thorner, J. W. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.8.3460-3469.1992 · Cited by 82 · cited 2×
“S. cerevisiae carries two redundant calcineurin A genes, CNA1 and CNA2 (12, 49), and a single copy of the calcineurin B gene, CNB1 (13, 42).”
Background
TheCandida albicans PKC1 gene encodes a protein kinase C homolog necessary for cellular integrity but not dimorphism
Paravicini, G., Mendoza-Losana, A., Antonsson, B. E., Cooper, M., Losberger, C., & Payton, M. A. (1996) · Yeast · doi:10.1002/(sici)1097-0061(19960630)12:8 · Cited by 80
Susceptibility of Cryptococcus neoformans to Photodynamic Inactivation Is Associated with Cell Wall Integrity
Fuchs, B. B., Tegos, G. P., Hamblin, M. R., & Mylonakis, E. E. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00121-07 · Cited by 75 · cited 1×
“A rom2 deletion strain is also sensitive to thermal stress in combination with an additional cell wall stressor such as Congo red or sodium dodecyl sulfate (22).”
BackgroundSelf-citation
Deletion of the Aspergillus fumigatus Gene Encoding the Ras-Related Protein RhbA Reduces Virulence in a Model of Invasive Pulmonary Aspergillosis
Panepinto, J. C., Oliver, B. G., Fortwendel, J. R., Smith, D. L. H., Askew, D. S., & Rhodes, J. C. (2003) · Infection and Immunity · doi:10.1128/iai.71.5.2819-2826.2003 · Cited by 72 · cited 1×
“fumigatus, where an rhbA deletion mutant strain is sensitivity to rapamycin (59).”
Background
Ssk2 Mitogen-Activated Protein Kinase Kinase Kinase Governs Divergent Patterns of the Stress-Activated Hog1 Signaling Pathway in Cryptococcus neoformans
Bahn, Y., Geunes-Boyer, S., & Heitman, J. (2007) · Eukaryotic Cell · doi:10.1128/ec.00349-07 · Cited by 71 · cited 1×
“However, the HOG pathway of pathogenic fungi in which it has been studied is broader in scope than governing just the osmotic response, because it also regulates stress responses to stimuli such as oxidative stress, UV light, heavy metals, and high temperature (1, 4, 7).”
Background
A small G protein Rhb1 and a GTPase-activating protein Tsc2 involved in nitrogen starvation-induced morphogenesis and cell wall integrity of Candida albicans
Tsao, C.-C., Chen, Y.-T., & Lan, C. (2008) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2008.11.008 · Cited by 56 · cited 4×
“albicans cells exposed to rapamycin exhibit enhanced phosphorylation of Mkc1 (encoded by a SLT2/MPK1 homolog) (Table 1), suggesting that TOR influences the CWI pathway (75).”
BackgroundInfluential
The Rgd1p Rho GTPase-Activating Protein and the Mid2p Cell Wall Sensor Are Required at Low pH for Protein Kinase C Pathway Activation and Cell Survival in Saccharomyces cerevisiae
Claret, S. B., Gatti, X., Doignon, F., Thoraval, D. H., & Crouzet, M. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.8.1375-1386.2005 · Cited by 54 · cited 14×
“Thus, there is potentially a sensor other than Wsc1 and Mid2 to initiate the signal cascade or a lateral influence.”
BackgroundInfluential
The calmodulin‐dependent protein phosphatase catalytic subunit (calcineurin A) is an essential gene in Aspergillus nidulans.
Rasmussen, C. D., Garen, C. R., Brining, S. K., Kincaid, R. L., Means, R. L., & Means, A. R. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06703.x · Cited by 50
RGD1, encoding a RhoGAP involved in low-pH survival, is an Msn2p/Msn4p regulated gene in Saccharomyces cerevisiae
Gatti, X., de Bettignies, G., Claret, S. B., Doignon, F., Crouzet, M., & Thoraval, D. H. (2005) · Gene · doi:10.1016/j.gene.2005.03.034 · Cited by 22 · cited 1×
“Furthermore, the expression of RGD1 under acidic shock conditions was Hog1 dependent (25).”
Background
The Synthetic Genetic Network around PKC1 Identifies Novel Modulators and Components of Protein Kinase C Signaling in Saccharomyces cerevisiae
Krause, S. A., Xu, H., & Gray, J. V. (2008) · Eukaryotic Cell · doi:10.1128/ec.00222-08 · Cited by 22 · cited 1×
“cerevisiae PKC1 reveals several genes that influence the CWI pathways but are not themselves CWI pathway genes (41).”
Background
Overactivation of the Protein Kinase C-Signaling Pathway Suppresses the Defects of Cells Lacking the Rho3/Rho4-GAP Rgd1p in Saccharomyces cerevisiae
de Bettignies, G., Thoraval, D. H., Morel, C., Peypouquet, M., & Crouzet, M. (2001) · Genetics · doi:10.1093/genetics/159.4.1435 · Cited by 21
Insight into the Role of HOG Pathway Components Ssk2p, Pbs2p, and Hog1p in the Opportunistic Yeast Candida lusitaniae
Boisnard, S., Ruprich‐Robert, G., Florent, M., Silva, B. D., Chapeland‐Leclerc, F., & Papon, N. (2008) · Eukaryotic Cell · doi:10.1128/ec.00262-08 · Cited by 11 · cited 1×
“However, the HOG pathway of pathogenic fungi in which it has been studied is broader in scope than governing just the osmotic response, because it also regulates stress responses to stimuli such as oxidative stress, UV light, heavy metals, and high temperature (1, 4, 7).”
Background
De las penas
Moncayo, L. A. (1977) · Cited by 9

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Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae
Conrad, M., Schothorst, J., Kankipati, H. N., Zeebroeck, G. V., Rubio‐Texeira, M., & Thevelein, J. M. (2014) · FEMS Microbiology Reviews · doi:10.1111/1574-6976.12065 · Cited by 630
“…the cell wall integrity (CWI) pathway, a major stress-response pathway in yeast that controls actin polarization and cell wall expansion in response to various stress conditions, including heat, caffeine, nutrient starvation, cell wall damage, and actin perturbation (Fuchs & Mylonakis, 2009).”
Background
Regulatory circuitry governing fungal development, drug resistance, and disease.
Shapiro, R. S., Robbins, N., & Cowen, L. E. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00045-10 · Cited by 576
“cerevisiae, Pkc1, is essential under standard growth conditions and regulates the maintenance of cell wall integrity during growth and morphogenesis and in response to cell wall stress (195, 322, 650).”
Background
PKC Signaling Regulates Drug Resistance of the Fungal Pathogen Candida albicans via Circuitry Comprised of Mkc1, Calcineurin, and Hsp90
LaFayette, S. L., Collins, C., Zaas, A. K., Schell, W. A., Betancourt-Quiroz, M., Gunatilaka, A. A. L., Perfect, J. R., & Cowen, L. E. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001069 · Cited by 329
“cerevisiae that is essential under standard growth conditions and regulates maintenance of cell wall integrity during growth, morphogenesis, and response to cell wall stress [28,29,30,31].”
Background
Molecular mechanisms of Saccharomyces cerevisiae stress adaptation and programmed cell death in response to acetic acid
Giannattasio, S., Guaragnella, N., Ždralević, M., & Marra, E. (2013) · Frontiers in Microbiology · doi:10.3389/fmicb.2013.00033 · Cited by 197
“Acetic acid challenge at low pH causes activation of two mitogen-activated protein (MAP) kinases, Hog1p, involved in the high-osmolarity glycerol (HOG) signaling pathway (Hohmann, 2009) and Slt2p involved in cell wall integrity pathway (Fuchs and Mylonakis, 2009).”
Background
The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence
Valiante, V., Macheleidt, J., Föge, M., & Brakhage, A. A. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00325 · Cited by 189
“For S. cerevisiae, cross talk between the CWI pathway and other signal transduction pathways under different conditions have been described (Fuchs and Mylonakis, 2009), but in A. fumigatus this interesting and complex field of research is just emerging.”
Background

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Authors: Fuchs, B. B., & Mylonakis, E.
Affiliations: Harvard University (US)
ORCID: Fuchs, Beth Burgwyn
Mylonakis, Eleftherios
Venue: Eukaryotic Cell
Publisher: American Society for Microbiology
Published: 2009-11
Volume: 8
Issue: 11
Pages: 1616-1625
ISSN: 1535-9778 (ISSN-L)
1535-9786
DOI: 10.1128/ec.00193-09
PMC: PMC2772411
OpenAlex: W2136493024
Cited by: 266
References: 87
Citations by year: 2026: 17 · 2025: 14 · 2024: 12 · 2023: 9 · 2022: 21 · 2021: 17 · 2020: 22 · 2019: 12 · 2018: 22 · 2017: 16 · 2016: 17 · 2015: 20 · 2014: 17 · 2013: 12 · 2012: 14
FWCI: 0.97
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Eukaryotic Cell (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases (R21AI079569, R01AI075286)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords: stress response, MAPK signaling, pathway crosstalk, TOR signaling, calcineurin signaling, high-osmolarity glycerol pathway, cAMP/protein kinase A pathway, transcription factors, actin organization, cell wall biosynthesis, Saccharomyces cerevisiae, pH stress, osmotic stress, oxidative stress, nutrient deprivation
MeSH terms: Cell Wall, Fungal Proteins, Fungi, Saccharomyces cerevisiae, Stress, Physiological, Signal Transduction, Receptor Cross-Talk

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Our Paths Might Cross: the Role of the Fungal Cell Wall Integrity Pathway in Stress Response and Cross Talk with Other Stress Response Pathways

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