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The Fungal Cell Wall Integrity Pathway
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The Fungal Cell Wall Integrity Pathway

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Genomics, Genetics and Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 57671

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. María Molina

E-Mail Website
Guest Editor
Dpto. Microbiología y Parasitología, Fac. de Famacia, Universidad Complutense de Madrid, Madrid, Spain
Interests: yeast cell wall; MAPK signaling; humanized yeast models
Dr. Humberto Martín

E-Mail Website
Guest Editor
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
Interests: yeast genetics; MAPK signaling; antifungal drug development

Special Issue Information

Dear Colleagues,

Adaptation to external changes is necessary for all cells to survive and thrive in diverse environments. Key to these responses are the MAPK-mediated signaling pathways, intracellular communication routes that sense stimuli at the cell surface, and are ubiquitous in all eukaryotic organisms. In the case of fungi, MAPKs mediate essential processes such as adaptation to environmental stresses, morphology regulation, or developmental processes. First studied in the early nineties in Saccharomyces cerevisiae, the fungal cell wall integrity (CWI) pathway has proven to be a central MAPK-mediated signaling cascade conserved in the fungal kingdom. It is essential for cells to sense cell wall perturbing conditions and mount the appropriate salvage response. Understanding this CWI pathway-mediated compensatory mechanism is key for the development of cell wall-targeted antifungal therapies. Moreover, its functional roles go beyond the maintenance of this essential structure, reaching many other physiological aspects that have major implications in development or virulence.

The Journal of Fungi is aware of the importance of this topic and thus invites authors to propose original research articles or reviews related to the fungal CWI pathway.

Dr. María Molina
Dr. Humberto Martín
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Fungi is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MAPK
  • Cell wall
  • signaling
  • fungi

Published Papers (19 papers)

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Editorial

Jump to: Research, Review

5 pages, 226 KiB  
Editorial
Special Issue “The Fungal Cell Wall Integrity Pathway”
by Humberto Martín and María Molina
J. Fungi 2023, 9(3), 293; https://doi.org/10.3390/jof9030293 - 24 Feb 2023
Cited by 1 | Viewed by 1271
Abstract
Adaptation to external changes is necessary for all cell types to survive and thrive in diverse environments [...] Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)

Research

Jump to: Editorial, Review

18 pages, 3539 KiB  
Article
Systematic Identification of Essential Genes Required for Yeast Cell Wall Integrity: Involvement of the RSC Remodelling Complex
by Ana Belén Sanz, Sonia Díez-Muñiz, Jennifer Moya, Yuliya Petryk, César Nombela, José M. Rodríguez-Peña and Javier Arroyo
J. Fungi 2022, 8(7), 718; https://doi.org/10.3390/jof8070718 - 08 Jul 2022
Cited by 2 | Viewed by 2059
Abstract
Conditions altering the yeast cell wall lead to the activation of an adaptive transcriptional response mainly governed by the cell wall integrity (CWI) mitogen-activated protein kinase (MAPK) pathway. Two high-throughput screenings were developed using the yTHC collection of yeast conditional mutant strains to [...] Read more.
Conditions altering the yeast cell wall lead to the activation of an adaptive transcriptional response mainly governed by the cell wall integrity (CWI) mitogen-activated protein kinase (MAPK) pathway. Two high-throughput screenings were developed using the yTHC collection of yeast conditional mutant strains to systematically identify essential genes related to cell wall integrity, and those required for the transcriptional program elicited by cell wall stress. Depleted expression of 52 essential genes resulted in hypersensitivity to the dye Calcofluor white, with chromatin organization, Golgi vesicle transport, rRNA processing, and protein glycosylation processes, as the most highly representative functional groups. Via a flow cytometry-based quantitative assay using a CWI reporter plasmid, 97 strains exhibiting reduced gene-reporter expression levels upon stress were uncovered, highlighting genes associated with RNA metabolism, transcription/translation, protein degradation, and chromatin organization. This screening also led to the discovery of 41 strains displaying a basal increase in CWI-associated gene expression, including mainly putative cell wall-related genes. Interestingly, several members of the RSC chromatin remodelling complex were uncovered in both screenings. Notably, Rsc9 was necessary to regulate the gene expression of CWI-related genes both under stress and non-stress conditions, suggesting distinct requirements of the RSC complex for remodelling particular genes. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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18 pages, 4300 KiB  
Article
Structure of the Yeast Cell Wall Integrity Sensor Wsc1 Reveals an Essential Role of Surface-Exposed Aromatic Clusters
by Philipp Schöppner, Anne Pia Lutz, Bernard Johannes Lutterbach, Stefan Brückner, Lars-Oliver Essen and Hans-Ulrich Mösch
J. Fungi 2022, 8(4), 379; https://doi.org/10.3390/jof8040379 - 08 Apr 2022
Cited by 5 | Viewed by 2620
Abstract
In the yeast Saccharomyces cerevisiae and other ascomycetes, the maintenance of cell wall integrity is governed by a family of plasma-membrane spanning sensors that include the Wsc-type proteins. These cell wall proteins apparently sense stress-induced mechanical forces at the cell surface and target [...] Read more.
In the yeast Saccharomyces cerevisiae and other ascomycetes, the maintenance of cell wall integrity is governed by a family of plasma-membrane spanning sensors that include the Wsc-type proteins. These cell wall proteins apparently sense stress-induced mechanical forces at the cell surface and target the cell wall integrity (CWI) signaling pathway, but the structural base for their sensor function is yet unknown. Here, we solved a high-resolution crystal structure of the extracellular cysteine-rich domain (CRD) of yeast Wsc1, which shows the characteristic PAN/Apple domain fold with two of the four Wsc1 disulfide bridges being conserved in other PAN domain cores. Given the general function of PAN domains in mediating protein–protein and protein–carbohydrate interactions, this finding underpins the importance of Wsc domains in conferring sensing and localization functions. Our Wsc1 CRD structure reveals an unusually high number of surface-exposed aromatic residues that are conserved in other fungal CRDs, and can be arranged into three solvent-exposed clusters. Mutational analysis demonstrates that two of the aromatic clusters are required for conferring S. cerevisiae Wsc1-dependent resistance to the glucan synthase inhibitor caspofungin, and the chitin-binding agents Congo red and Calcofluor white. These findings suggest an essential role of surface-exposed aromatic clusters in fungal Wsc-type sensors that might include an involvement in stress-induced sensor-clustering required to elicit appropriate cellular responses via the downstream CWI pathway. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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22 pages, 3996 KiB  
Article
Slt2 Is Required to Activate ER-Stress-Protective Mechanisms through TORC1 Inhibition and Hexosamine Pathway Activation
by Isabel E. Sánchez-Adriá, Gemma Sanmartín, Jose A. Prieto, Francisco Estruch and Francisca Randez-Gil
J. Fungi 2022, 8(2), 92; https://doi.org/10.3390/jof8020092 - 18 Jan 2022
Cited by 7 | Viewed by 3328
Abstract
Slt2, the MAPK of the cell wall integrity (CWI) pathway, connects different signaling pathways and performs different functions in the protective response of S. cerevisiae to stress. Previous work has evidenced the relation of the CWI pathway and the unfolded protein response (UPR), [...] Read more.
Slt2, the MAPK of the cell wall integrity (CWI) pathway, connects different signaling pathways and performs different functions in the protective response of S. cerevisiae to stress. Previous work has evidenced the relation of the CWI pathway and the unfolded protein response (UPR), a transcriptional program activated upon endoplasmic reticulum (ER) stress. However, the mechanisms of crosstalk between these pathways and the targets regulated by Slt2 under ER stress remain unclear. Here, we demonstrated that ectopic expression of GFA1, the gene encoding the first enzyme in the synthesis of UDP-GlcNAc by the hexosamine biosynthetic pathway (HBP) or supplementation of the growth medium with glucosamine (GlcN), increases the tolerance of slt2 mutant cells to different ER-stress inducers. Remarkably, GlcN also alleviates the sensitivity phenotype of cells lacking IRE1 or HAC1, the main actors in controlling the UPR. The exogenous addition of GlcN reduced the abundance of glycosylated proteins and triggered autophagy. We also found that TORC1, the central stress and growth controller, is inhibited by tunicamycin exposure in cells of the wild-type strain but not in those lacking Slt2. Consistent with this, the tunicamycin-induced activation of autophagy and the increased synthesis of ATP in response to ER stress were absent by knock-out of SLT2. Altogether, our data placed Slt2 as an essential actor of the ER stress response by regulating the HBP activity and the TORC1-dependent signaling. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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18 pages, 4675 KiB  
Article
Differential Requirement for the Cell Wall Integrity Sensor Wsc1p in Diploids Versus Haploids
by Allison E. Hall, Miriam Lisci and Mark D. Rose
J. Fungi 2021, 7(12), 1049; https://doi.org/10.3390/jof7121049 - 08 Dec 2021
Cited by 1 | Viewed by 2450
Abstract
The primary role of the Cell Wall Integrity Pathway (CWI) in Saccharomyces cerevisiae is monitoring the state of the cell wall in response to general life cycle stresses (growth and mating) and imposed stresses (temperature changes and chemicals). Of the five mechanosensor proteins [...] Read more.
The primary role of the Cell Wall Integrity Pathway (CWI) in Saccharomyces cerevisiae is monitoring the state of the cell wall in response to general life cycle stresses (growth and mating) and imposed stresses (temperature changes and chemicals). Of the five mechanosensor proteins monitoring cell wall stress, Wsc1p and Mid2p are the most important. We find that WSC1 has a stringent requirement in zygotes and diploids, unlike haploids, and differing from MID2’s role in shmoos. Diploids lacking WSC1 die frequently, independent of mating type. Death is due to loss of cell wall and plasma membrane integrity, which is suppressed by osmotic support. Overexpression of several CWI pathway components suppress wsc1∆ zygotic death, including WSC2, WSC3, and BEM2, as well as the Rho-GAPS, BEM3 and RGD2. Microscopic observations and suppression by BEM2 and BEM3 suggest that wsc1∆ zygotes die during bud emergence. Downstream in the CWI pathway, overexpression of a hyperactive protein kinase C (Pkc1p-R398P) causes growth arrest, and blocks the pheromone response. With moderate levels of Pkc1p-R398P, cells form zygotes and the wsc1∆ defect is suppressed. This work highlights functional differences in the requirement for Wsc1p in diploids Versus haploids and between Mid2p and Wsc1p during mating. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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19 pages, 2159 KiB  
Article
The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall
by Marina Valente Navarro, Yasmin Nascimento de Barros, Wilson Dias Segura, Alison Felipe Alencar Chaves, Grasielle Pereira Jannuzzi, Karen Spadari Ferreira, Patrícia Xander and Wagner Luiz Batista
J. Fungi 2021, 7(12), 1014; https://doi.org/10.3390/jof7121014 - 26 Nov 2021
Cited by 3 | Viewed by 1999
Abstract
Dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM), an endemic disease in Latin America with a high incidence in Brazil. This pathogen presents as infective mycelium at 25 °C in the soil, reverting to its pathogenic form when [...] Read more.
Dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM), an endemic disease in Latin America with a high incidence in Brazil. This pathogen presents as infective mycelium at 25 °C in the soil, reverting to its pathogenic form when inhaled by the mammalian host (37 °C). Among these dimorphic fungal species, dimorphism regulating histidine kinase (Drk1) plays an essential role in the morphological transition. These kinases are present in bacteria and fungi but absent in mammalian cells and are important virulence and cellular survival regulators. Hence, the purpose of this study was to investigate the role of PbDrk1 in the cell wall modulation of P. brasiliensis. We observed that PbDrk1 participates in fungal resistance to different cell wall-disturbing agents by reducing viability after treatment with iDrk1. To verify the role of PbDRK1 in cell wall morphogenesis, qPCR results showed that samples previously exposed to iDrk1 presented higher expression levels of several genes related to cell wall modulation. One of them was FKS1, a β-glucan synthase that showed a 3.6-fold increase. Furthermore, confocal microscopy analysis and flow cytometry showed higher β-glucan exposure on the cell surface of P. brasiliensis after incubation with iDrk1. Accordingly, through phagocytosis assays, a significantly higher phagocytic index was observed in yeasts treated with iDrk1 than the control group, demonstrating the role of PbDrk1 in cell wall modulation, which then becomes a relevant target to be investigated. In parallel, the immune response profile showed increased levels of proinflammatory cytokines. Finally, our data strongly suggest that PbDrk1 modulates cell wall component expression, among which we can identify β-glucan. Understanding this signalling pathway may be of great value for identifying targets of antifungal molecular activity since HKs are not present in mammals. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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25 pages, 5170 KiB  
Article
The Cell Wall Integrity Receptor Mtl1 Contributes to Articulate Autophagic Responses When Glucose Availability Is Compromised
by Sandra Montella-Manuel, Nuria Pujol-Carrion and Maria Angeles de la Torre-Ruiz
J. Fungi 2021, 7(11), 903; https://doi.org/10.3390/jof7110903 - 26 Oct 2021
Cited by 7 | Viewed by 1806
Abstract
Mtl1protein is a cell wall receptor belonging to the CWI pathway. Mtl1 function is related to glucose and oxidative stress signaling. In this report, we show data demonstrating that Mtl1 plays a critical role in the detection of a descent in glucose concentration, [...] Read more.
Mtl1protein is a cell wall receptor belonging to the CWI pathway. Mtl1 function is related to glucose and oxidative stress signaling. In this report, we show data demonstrating that Mtl1 plays a critical role in the detection of a descent in glucose concentration, in order to activate bulk autophagy machinery as a response to nutrient deprivation and to maintain cell survival in starvation conditions. Autophagy is a tightly regulated mechanism involving several signaling pathways. The data here show that in Saccharomyces cerevisiae, Mtl1 signals glucose availability to either Ras2 or Sch9 proteins converging in Atg1 phosphorylation and autophagy induction. TORC1 complex function is not involved in autophagy induction during the diauxic shift when glucose is limited. In this context, the GCN2 gene is required to regulate autophagy activation upon amino acid starvation independent of the TORC1 complex. Mtl1 function is also involved in signaling the autophagic degradation of mitochondria during the stationary phase through both Ras2 and Sch9, in a manner dependent on either Atg33 and Atg11 proteins and independent of the Atg32 protein, the mitophagy receptor. All of the above suggest a pivotal signaling role for Mtl1 in maintaining correct cell homeostasis function in periods of glucose scarcity in budding yeast. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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17 pages, 2316 KiB  
Article
Regulation of Pkc1 Hyper-Phosphorylation by Genotoxic Stress
by Li Liu, Jiri Veis, Wolfgang Reiter, Edwin Motari, Catherine E. Costello, John C. Samuelson, Gustav Ammerer and David E. Levin
J. Fungi 2021, 7(10), 874; https://doi.org/10.3390/jof7100874 - 17 Oct 2021
Cited by 5 | Viewed by 2903
Abstract
The cell wall integrity (CWI) signaling pathway is best known for its roles in cell wall biogenesis. However, it is also thought to participate in the response to genotoxic stress. The stress-activated protein kinase Mpk1 (Slt2, is activated by DNA damaging agents through [...] Read more.
The cell wall integrity (CWI) signaling pathway is best known for its roles in cell wall biogenesis. However, it is also thought to participate in the response to genotoxic stress. The stress-activated protein kinase Mpk1 (Slt2, is activated by DNA damaging agents through an intracellular mechanism that does not involve the activation of upstream components of the CWI pathway. Additional observations suggest that protein kinase C (Pkc1), the top kinase in the CWI signaling cascade, also has a role in the response to genotoxic stress that is independent of its recognized function in the activation of Mpk1. Pkc1 undergoes hyper-phosphorylation specifically in response to genotoxic stress; we have found that this requires the DNA damage checkpoint kinases Mec1 (Mitosis Entry Checkpoint) and Tel1 (TELomere maintenance), but not their effector kinases. We demonstrate that the casein kinase 1 (CK1) ortholog, Hrr25 (HO and Radiation Repair), previously implicated in the DNA damage transcriptional response, associates with Pkc1 under conditions of genotoxic stress. We also found that the induced association of Hrr25 with Pkc1 requires Mec1 and Tel1, and that Hrr25 catalytic activity is required for Pkc1-hyperphosphorylation, thereby delineating a pathway from the checkpoint kinases to Pkc1. We used SILAC mass spectrometry to identify three residues within Pkc1 the phosphorylation of which was stimulated by genotoxic stress. We mutated these residues as well as a collection of 13 phosphorylation sites within the regulatory domain of Pkc1 that fit the consensus for CK1 sites. Mutation of the 13 Pkc1 phosphorylation sites blocked hyper-phosphorylation and diminished RNR3 (RiboNucleotide Reductase) basal expression and induction by genotoxic stress, suggesting that Pkc1 plays a role in the DNA damage transcriptional response. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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19 pages, 8974 KiB  
Article
Defining Functions of Mannoproteins in Saccharomyces cerevisiae by High-Dimensional Morphological Phenotyping
by Farzan Ghanegolmohammadi, Hiroki Okada, Yaxuan Liu, Kaori Itto-Nakama, Shinsuke Ohnuki, Anna Savchenko, Erfei Bi, Satoshi Yoshida and Yoshikazu Ohya
J. Fungi 2021, 7(9), 769; https://doi.org/10.3390/jof7090769 - 17 Sep 2021
Cited by 6 | Viewed by 3124
Abstract
Mannoproteins are non-filamentous glycoproteins localized to the outermost layer of the yeast cell wall. The physiological roles of these structural components have not been completely elucidated due to the limited availability of appropriate tools. As the perturbation of mannoproteins may affect cell morphology, [...] Read more.
Mannoproteins are non-filamentous glycoproteins localized to the outermost layer of the yeast cell wall. The physiological roles of these structural components have not been completely elucidated due to the limited availability of appropriate tools. As the perturbation of mannoproteins may affect cell morphology, we investigated mannoprotein mutants in Saccharomyces cerevisiae via high-dimensional morphological phenotyping. The mannoprotein mutants were morphologically classified into seven groups using clustering analysis with Gaussian mixture modeling. The pleiotropic phenotypes of cluster I mutant cells (ccw12Δ) indicated that CCW12 plays major roles in cell wall organization. Cluster II (ccw14Δ, flo11Δ, srl1Δ, and tir3Δ) mutants exhibited altered mother cell size and shape. Mutants of cluster III and IV exhibited no or very small morphological defects. Cluster V (dse2Δ, egt2Δ, and sun4Δ) consisted of endoglucanase mutants with cell separation defects due to incomplete septum digestion. The cluster VI mutant cells (ecm33Δ) exhibited perturbation of apical bud growth. Cluster VII mutant cells (sag1Δ) exhibited differences in cell size and actin organization. Biochemical assays further confirmed the observed morphological defects. Further investigations based on various omics data indicated that morphological phenotyping is a complementary tool that can help with gaining a deeper understanding of the functions of mannoproteins. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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Graphical abstract

22 pages, 3403 KiB  
Article
Clotrimazole-Induced Oxidative Stress Triggers Novel Yeast Pkc1-Independent Cell Wall Integrity MAPK Pathway Circuitry
by Ángela Sellers-Moya, Marcos Nuévalos, María Molina and Humberto Martín
J. Fungi 2021, 7(8), 647; https://doi.org/10.3390/jof7080647 - 09 Aug 2021
Cited by 7 | Viewed by 2660
Abstract
Azoles are one of the most widely used drugs to treat fungal infections. To further understand the fungal response to azoles, we analyzed the MAPK circuitry of the model yeast Saccharomyces cerevisiae that operates under treatment with these antifungals. Imidazoles, and particularly clotrimazole, [...] Read more.
Azoles are one of the most widely used drugs to treat fungal infections. To further understand the fungal response to azoles, we analyzed the MAPK circuitry of the model yeast Saccharomyces cerevisiae that operates under treatment with these antifungals. Imidazoles, and particularly clotrimazole, trigger deeper changes in MAPK phosphorylation than triazoles, involving a reduction in signaling through the mating pathway and the activation of the MAPKs Hog1 and Slt2 from the High-Osmolarity Glycerol (HOG) and the Cell Wall Integrity (CWI) pathways, respectively. Clotrimazole treatment leads to actin aggregation, mitochondrial alteration, and oxidative stress, which is essential not only for the activation of both MAPKs, but also for the appearance of a low-mobility form of Slt2 caused by additional phosphorylation to that occurring at the conserved TEY activation motif. Clotrimazole-induced ROS production and Slt2 phosphorylation are linked to Tpk3-mediated PKA activity. Resistance to clotrimazole depends on HOG and CWI-pathway-mediated stress responses. However, Pkc1 and other proteins acting upstream in the pathway are not critical for the activation of the Slt2 MAPK module, suggesting a novel rewiring of signaling through the CWI pathway. We further show that the strong impact of azole treatment on MAPK signaling is conserved in other yeast species. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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18 pages, 4400 KiB  
Article
Specific Functional Features of the Cell Integrity MAP Kinase Pathway in the Dimorphic Fission Yeast Schizosaccharomyces japonicus
by Elisa Gómez-Gil, Alejandro Franco, Beatriz Vázquez-Marín, Francisco Prieto-Ruiz, Armando Pérez-Díaz, Jero Vicente-Soler, Marisa Madrid, Teresa Soto and José Cansado
J. Fungi 2021, 7(6), 482; https://doi.org/10.3390/jof7060482 - 14 Jun 2021
Cited by 3 | Viewed by 2872
Abstract
Mitogen activated protein kinase (MAPK) signaling pathways execute essential functions in eukaryotic organisms by transducing extracellular stimuli into adaptive cellular responses. In the fission yeast model Schizosaccharomyces pombe the cell integrity pathway (CIP) and its core effector, MAPK Pmk1, play a key role [...] Read more.
Mitogen activated protein kinase (MAPK) signaling pathways execute essential functions in eukaryotic organisms by transducing extracellular stimuli into adaptive cellular responses. In the fission yeast model Schizosaccharomyces pombe the cell integrity pathway (CIP) and its core effector, MAPK Pmk1, play a key role during regulation of cell integrity, cytokinesis, and ionic homeostasis. Schizosaccharomyces japonicus, another fission yeast species, shows remarkable differences with respect to S. pombe, including a robust yeast to hyphae dimorphism in response to environmental changes. We show that the CIP MAPK module architecture and its upstream regulators, PKC orthologs Pck1 and Pck2, are conserved in both fission yeast species. However, some of S. pombe’s CIP-related functions, such as cytokinetic control and response to glucose availability, are regulated differently in S. japonicus. Moreover, Pck1 and Pck2 antagonistically regulate S. japonicus hyphal differentiation through fine-tuning of Pmk1 activity. Chimeric MAPK-swapping experiments revealed that S. japonicus Pmk1 is fully functional in S. pombe, whereas S. pombe Pmk1 shows a limited ability to execute CIP functions and promote S. japonicus mycelial development. Our findings also suggest that a modified N-lobe domain secondary structure within S. japonicus Pmk1 has a major influence on the CIP signaling features of this evolutionarily diverged fission yeast. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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17 pages, 2461 KiB  
Article
A Three-Dimensional Model of the Yeast Transmembrane Sensor Wsc1 Obtained by SMA-Based Detergent-Free Purification and Transmission Electron Microscopy
by Natalia Voskoboynikova, Maria Karlova, Rainer Kurre, Armen Y. Mulkidjanian, Konstantin V. Shaitan, Olga S. Sokolova, Heinz-Jürgen Steinhoff and Jürgen J. Heinisch
J. Fungi 2021, 7(2), 118; https://doi.org/10.3390/jof7020118 - 05 Feb 2021
Cited by 10 | Viewed by 3757
Abstract
The cell wall sensor Wsc1 belongs to a small family of transmembrane proteins, which are crucial to sustain cell integrity in yeast and other fungi. Wsc1 acts as a mechanosensor of the cell wall integrity (CWI) signal transduction pathway which responds to external [...] Read more.
The cell wall sensor Wsc1 belongs to a small family of transmembrane proteins, which are crucial to sustain cell integrity in yeast and other fungi. Wsc1 acts as a mechanosensor of the cell wall integrity (CWI) signal transduction pathway which responds to external stresses. Here we report on the purification of Wsc1 by its trapping in water-soluble polymer-stabilized lipid nanoparticles, obtained with an amphipathic styrene-maleic acid (SMA) copolymer. The latter was employed to transfer tagged sensors from their native yeast membranes into SMA/lipid particles (SMALPs), which allows their purification in a functional state, i.e., avoiding denaturation. The SMALPs composition was characterized by fluorescence correlation spectroscopy, followed by two-dimensional image acquisition from single particle transmission electron microscopy to build a three-dimensional model of the sensor. The latter confirms that Wsc1 consists of a large extracellular domain connected to a smaller intracellular part by a single transmembrane domain, which is embedded within the hydrophobic moiety of the lipid bilayer. The successful extraction of a sensor from the yeast plasma membrane by a detergent-free procedure into a native-like membrane environment provides new prospects for in vitro structural and functional studies of yeast plasma proteins which are likely to be applicable to other fungi, including plant and human pathogens. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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Review

Jump to: Editorial, Research

24 pages, 1251 KiB  
Review
Cell Wall Integrity and Its Industrial Applications in Filamentous Fungi
by Akira Yoshimi, Ken Miyazawa, Moriyuki Kawauchi and Keietsu Abe
J. Fungi 2022, 8(5), 435; https://doi.org/10.3390/jof8050435 - 23 Apr 2022
Cited by 9 | Viewed by 3548
Abstract
Signal transduction pathways regulating cell wall integrity (CWI) in filamentous fungi have been studied taking into account findings in budding yeast, and much knowledge has been accumulated in recent years. Given that the cell wall is essential for viability in fungi, its architecture [...] Read more.
Signal transduction pathways regulating cell wall integrity (CWI) in filamentous fungi have been studied taking into account findings in budding yeast, and much knowledge has been accumulated in recent years. Given that the cell wall is essential for viability in fungi, its architecture has been analyzed in relation to virulence, especially in filamentous fungal pathogens of plants and humans. Although research on CWI signaling in individual fungal species has progressed, an integrated understanding of CWI signaling in diverse fungi has not yet been achieved. For example, the variety of sensor proteins and their functional differences among different fungal species have been described, but the understanding of their general and species-specific biological functions is limited. Our long-term research interest is CWI signaling in filamentous fungi. Here, we outline CWI signaling in these fungi, from sensor proteins required for the recognition of environmental changes to the regulation of cell wall polysaccharide synthesis genes. We discuss the similarities and differences between the functions of CWI signaling factors in filamentous fungi and in budding yeast. We also describe the latest findings on industrial applications, including those derived from studies on CWI signaling: the development of antifungal agents and the development of highly productive strains of filamentous fungi with modified cell surface characteristics by controlling cell wall biogenesis. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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25 pages, 1239 KiB  
Review
Substrates of the MAPK Slt2: Shaping Yeast Cell Integrity
by Gema González-Rubio, Lucía Sastre-Vergara, María Molina, Humberto Martín and Teresa Fernández-Acero
J. Fungi 2022, 8(4), 368; https://doi.org/10.3390/jof8040368 - 04 Apr 2022
Cited by 13 | Viewed by 3467
Abstract
The cell wall integrity (CWI) MAPK pathway of budding yeast Saccharomyces cerevisiae is specialized in responding to cell wall damage, but ongoing research shows that it participates in many other stressful conditions, suggesting that it has functional diversity. The output of this pathway [...] Read more.
The cell wall integrity (CWI) MAPK pathway of budding yeast Saccharomyces cerevisiae is specialized in responding to cell wall damage, but ongoing research shows that it participates in many other stressful conditions, suggesting that it has functional diversity. The output of this pathway is mainly driven by the activity of the MAPK Slt2, which regulates important processes for yeast physiology such as fine-tuning of signaling through the CWI and other pathways, transcriptional activation in response to cell wall damage, cell cycle, or determination of the fate of some organelles. To this end, Slt2 precisely phosphorylates protein substrates, modulating their activity, stability, protein interaction, and subcellular localization. Here, after recapitulating the methods that have been employed in the discovery of proteins phosphorylated by Slt2, we review the bona fide substrates of this MAPK and the growing set of candidates still to be confirmed. In the context of the complexity of MAPK signaling regulation, we discuss how Slt2 determines yeast cell integrity through phosphorylation of these substrates. Increasing data from large-scale analyses and the available methodological approaches pave the road to early identification of new Slt2 substrates and functions. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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31 pages, 2747 KiB  
Review
The Fission Yeast Cell Integrity Pathway: A Functional Hub for Cell Survival upon Stress and Beyond
by José Cansado, Teresa Soto, Alejandro Franco, Jero Vicente-Soler and Marisa Madrid
J. Fungi 2022, 8(1), 32; https://doi.org/10.3390/jof8010032 - 30 Dec 2021
Cited by 8 | Viewed by 2783
Abstract
The survival of eukaryotic organisms during environmental changes is largely dependent on the adaptive responses elicited by signal transduction cascades, including those regulated by the Mitogen-Activated Protein Kinase (MAPK) pathways. The Cell Integrity Pathway (CIP), one of the three MAPK pathways found in [...] Read more.
The survival of eukaryotic organisms during environmental changes is largely dependent on the adaptive responses elicited by signal transduction cascades, including those regulated by the Mitogen-Activated Protein Kinase (MAPK) pathways. The Cell Integrity Pathway (CIP), one of the three MAPK pathways found in the simple eukaryote fission of yeast Schizosaccharomyces pombe, shows strong homology with mammalian Extracellular signal-Regulated Kinases (ERKs). Remarkably, studies over the last few decades have gradually positioned the CIP as a multi-faceted pathway that impacts multiple functional aspects of the fission yeast life cycle during unperturbed growth and in response to stress. They include the control of mRNA-stability through RNA binding proteins, regulation of calcium homeostasis, and modulation of cell wall integrity and cytokinesis. Moreover, distinct evidence has disclosed the existence of sophisticated interplay between the CIP and other environmentally regulated pathways, including Stress-Activated MAP Kinase signaling (SAPK) and the Target of Rapamycin (TOR). In this review we present a current overview of the organization and underlying regulatory mechanisms of the CIP in S. pombe, describe its most prominent functions, and discuss possible targets of and roles for this pathway. The evolutionary conservation of CIP signaling in the dimorphic fission yeast S. japonicus will also be addressed. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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22 pages, 1541 KiB  
Review
The CWI Pathway: A Versatile Toolbox to Arrest Cell-Cycle Progression
by Inma Quilis, Mercè Gomar-Alba and Juan Carlos Igual
J. Fungi 2021, 7(12), 1041; https://doi.org/10.3390/jof7121041 - 04 Dec 2021
Cited by 8 | Viewed by 3066
Abstract
Cell-signaling pathways are essential for cells to respond and adapt to changes in their environmental conditions. The cell-wall integrity (CWI) pathway of Saccharomyces cerevisiae is activated by environmental stresses, compounds, and morphogenetic processes that compromise the cell wall, orchestrating the appropriate cellular response [...] Read more.
Cell-signaling pathways are essential for cells to respond and adapt to changes in their environmental conditions. The cell-wall integrity (CWI) pathway of Saccharomyces cerevisiae is activated by environmental stresses, compounds, and morphogenetic processes that compromise the cell wall, orchestrating the appropriate cellular response to cope with these adverse conditions. During cell-cycle progression, the CWI pathway is activated in periods of polarized growth, such as budding or cytokinesis, regulating cell-wall biosynthesis and the actin cytoskeleton. Importantly, accumulated evidence has indicated a reciprocal regulation of the cell-cycle regulatory system by the CWI pathway. In this paper, we describe how the CWI pathway regulates the main cell-cycle transitions in response to cell-surface perturbance to delay cell-cycle progression. In particular, it affects the Start transcriptional program and the initiation of DNA replication at the G1/S transition, and entry and progression through mitosis. We also describe the involvement of the CWI pathway in the response to genotoxic stress and its connection with the DNA integrity checkpoint, the mechanism that ensures the correct transmission of genetic material and cell survival. Thus, the CWI pathway emerges as a master brake that stops cell-cycle progression when cells are coping with distinct unfavorable conditions. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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12 pages, 888 KiB  
Review
Cell Wall Integrity Pathway Involved in Morphogenesis, Virulence and Antifungal Susceptibility in Cryptococcus neoformans
by Haroldo Cesar de Oliveira, Suelen Andreia Rossi, Irene García-Barbazán, Óscar Zaragoza and Nuria Trevijano-Contador
J. Fungi 2021, 7(10), 831; https://doi.org/10.3390/jof7100831 - 05 Oct 2021
Cited by 9 | Viewed by 2994
Abstract
Due to its location, the fungal cell wall is the compartment that allows the interaction with the environment and/or the host, playing an important role during infection as well as in different biological functions such as cell morphology, cell permeability and protection against [...] Read more.
Due to its location, the fungal cell wall is the compartment that allows the interaction with the environment and/or the host, playing an important role during infection as well as in different biological functions such as cell morphology, cell permeability and protection against stress. All these processes involve the activation of signaling pathways within the cell. The cell wall integrity (CWI) pathway is the main route responsible for maintaining the functionality and proper structure of the cell wall. This pathway is highly conserved in the fungal kingdom and has been extensively characterized in Saccharomyces cerevisiae. However, there are still many unknown aspects of this pathway in the pathogenic fungi, such as Cryptococcus neoformans. This yeast is of particular interest because it is found in the environment, but can also behave as pathogen in multiple organisms, including vertebrates and invertebrates, so it has to adapt to multiple factors to survive in multiple niches. In this review, we summarize the components of the CWI pathway in C. neoformans as well as its involvement in different aspects such as virulence factors, morphological changes, and its role as target for antifungal therapies among others. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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23 pages, 1071 KiB  
Review
Fungal Cell Wall Proteins and Signaling Pathways Form a Cytoprotective Network to Combat Stresses
by Chibuike Ibe and Carol A. Munro
J. Fungi 2021, 7(9), 739; https://doi.org/10.3390/jof7090739 - 08 Sep 2021
Cited by 25 | Viewed by 5302
Abstract
Candida species are part of the normal flora of humans, but once the immune system of the host is impaired and they escape from commensal niches, they shift from commensal to pathogen causing candidiasis. Candida albicans remains the primary cause of candidiasis, accounting [...] Read more.
Candida species are part of the normal flora of humans, but once the immune system of the host is impaired and they escape from commensal niches, they shift from commensal to pathogen causing candidiasis. Candida albicans remains the primary cause of candidiasis, accounting for about 60% of the global candidiasis burden. The cell wall of C. albicans and related fungal pathogens forms the interface with the host, gives fungal cells their shape, and also provides protection against stresses. The cell wall is a dynamic organelle with great adaptive flexibility that allows remodeling, morphogenesis, and changes in its components in response to the environment. It is mainly composed of the inner polysaccharide rich layer (chitin, and β-glucan) and the outer protein coat (mannoproteins). The highly glycosylated protein coat mediates interactions between C. albicans cells and their environment, including reprograming of wall architecture in response to several conditions, such as carbon source, pH, high temperature, and morphogenesis. The mannoproteins are also associated with C. albicans adherence, drug resistance, and virulence. Vitally, the mannoproteins contribute to cell wall construction and especially cell wall remodeling when cells encounter physical and chemical stresses. This review describes the interconnected cell wall integrity (CWI) and stress-activated pathways (e.g., Hog1, Cek1, and Mkc1 mediated pathways) that regulates cell wall remodeling and the expression of some of the mannoproteins in C. albicans and other species. The mannoproteins of the surface coat is of great importance to pathogen survival, growth, and virulence, thus understanding their structure and function as well as regulatory mechanisms can pave the way for better management of candidiasis. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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18 pages, 1088 KiB  
Review
The Role of the Cell Integrity Pathway in Septum Assembly in Yeast
by Cesar Roncero, Rubén Celador, Noelia Sánchez, Patricia García and Yolanda Sánchez
J. Fungi 2021, 7(9), 729; https://doi.org/10.3390/jof7090729 - 06 Sep 2021
Cited by 7 | Viewed by 3461
Abstract
Cytokinesis divides a mother cell into two daughter cells at the end of each cell cycle and proceeds via the assembly and constriction of a contractile actomyosin ring (CAR). Ring constriction promotes division furrow ingression, after sister chromatids are segregated to opposing sides [...] Read more.
Cytokinesis divides a mother cell into two daughter cells at the end of each cell cycle and proceeds via the assembly and constriction of a contractile actomyosin ring (CAR). Ring constriction promotes division furrow ingression, after sister chromatids are segregated to opposing sides of the cleavage plane. Cytokinesis contributes to genome integrity because the cells that fail to complete cytokinesis often reduplicate their chromosomes. While in animal cells, the last steps of cytokinesis involve extracellular matrix remodelling and mid-body abscission, in yeast, CAR constriction is coupled to the synthesis of a polysaccharide septum. To preserve cell integrity during cytokinesis, fungal cells remodel their cell wall through signalling pathways that connect receptors to downstream effectors, initiating a cascade of biological signals. One of the best-studied signalling pathways is the cell wall integrity pathway (CWI) of the budding yeast Saccharomyces cerevisiae and its counterpart in the fission yeast Schizosaccharomyces pombe, the cell integrity pathway (CIP). Both are signal transduction pathways relying upon a cascade of MAP kinases. However, despite strong similarities in the assembly of the septa in both yeasts, there are significant mechanistic differences, including the relationship of this process with the cell integrity signalling pathways. Full article
(This article belongs to the Special Issue The Fungal Cell Wall Integrity Pathway)
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