Genetic dissection of the signaling pathway required for the cell wall integrity checkpoint

Sukegawa, Yuko; Negishi, Takeharu; Kikuchi, Yo; Ishii, Keiko; Imanari, Miyuki; Ghanegolmohammadi, Farzan; Nogami, Satoru; Ohya, Yoshikazu

doi:10.1242/jcs.219063

Cited by 6 publications

(7 citation statements)

References 69 publications

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“…Under cell wall stress, SakA also physically interacts with the CWI MAPK, MpkA, and the PtcB MAPK phosphatase, suggesting a close connection between the HOG and CWI pathways. Cross-talk between the HOG and CWI pathways has been observed in several fungal species, including S. cerevisiae, Candida albicans, Fusarium graminearum, and Pyrenophora graminea (56)(57)(58)(59)(60)(61)(62)(63)(64). Now, we show that the absence of these two HOG pathwayassociated MAPKs, MpkC and SakA, abolishes the remodeling of the phosphoproteome seen in the wild-type fungus in response to cell wall damage, and we also reveal novel proteins potentially involved in cell wall stress response.…”

Section: Discussionsupporting

confidence: 54%

“…It is possible that A. fumigatus AsgA is similarly involved in some aspects of the cell wall damage response. In S. cerevisiae, the forkhead family transcription factor Fkh2 is involved in the activation of early-firing replication (68) and Fkh2 mutations suppress the checkpoint-defective phenotype of both HOG and cell wall integrity MAPK mutations (63). Therefore, the A. fumigatus homologue, FkhA, could be a putative CWI checkpoint for cell cycle progression in A. fumigatus.…”

Section: Discussionmentioning

confidence: 99%

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The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

Mattos

Silva

Valero

et al. 2020

mBio

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The filamentous fungus Aspergillus fumigatus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global A. fumigatus phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. IMPORTANCE Aspergillus fumigatus is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the ΔsakA and ΔmpkC A. fumigatus and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

Mattos

Silva

Valero

et al. 2020

mBio

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“…Importantly, in the absence of Slt2, Hcm1 is partially stabilized, similar to that observed in the nonphosphorylatable Hcm1 mutant [64]. All these observations have led to the suggestion that MAPK Slt2 triggers Hcm1 degradation by phosphorylation at Ser 61 , Ser 65 , and Ser 66 in response to cell-wall damage, eventually inducing the blockage of cell-cycle progression in G2/M. Supporting this, more recently, it has been reported that mutant strains in all components of the MAPK cascade are defective in blocking cell-cycle progression, as deduced from the presence of SPB separation under cell-wall stress conditions [65].…”

Section: The Cwi (Cell-wall Integrity) Checkpointmentioning

confidence: 52%

“…When the CWI checkpoint is triggered by cell-wall damage, the cellular levels of Hcm1 drop dramatically. This regulation occurs through a post-transcriptional mechanism involving the phosphorylation of at least Ser 61 , Ser 65 , and Ser 66 , which likely destabilizes the protein. As a consequence, the transcription of many genes regulated by Hcm1 (including the FKH2 and NDD1 genes) is impaired.…”

Section: The Cwi (Cell-wall Integrity) Checkpointmentioning

confidence: 99%

“…All these observations have led to the suggestion that MAPK Slt2 triggers Hcm1 degradation by phosphorylation at Ser 61 , Ser 65 , and Ser 66 in response to cell-wall damage, eventually inducing the blockage of cell-cycle progression in G2/M. Supporting this, more recently, it has been reported that mutant strains in all components of the MAPK cascade are defective in blocking cell-cycle progression, as deduced from the presence of SPB separation under cell-wall stress conditions [65]. Future work is necessary to demonstrate whether Hcm1 is indeed a substrate for Slt2 kinase, and to evaluate the relevance of this regulation in the response to cell-wall damage.…”

Section: The Cwi (Cell-wall Integrity) Checkpointmentioning

confidence: 99%

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The CWI Pathway: A Versatile Toolbox to Arrest Cell-Cycle Progression

Quilis

Gomar-Alba

Igual

2021

JoF

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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.

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Genome-Wide Identification, Evolutionary and Expression Analysis of Cyclin-Dependent Kinase Gene Family Members in Moso Bamboo (Phyllostachys edulis)

Dong,

Lan,

Liu

et al. 2024

J Plant Growth Regul

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Genetic dissection of the signaling pathway required for the cell wall integrity checkpoint

Cited by 6 publications

References 69 publications

The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

The CWI Pathway: A Versatile Toolbox to Arrest Cell-Cycle Progression

Genome-Wide Identification, Evolutionary and Expression Analysis of Cyclin-Dependent Kinase Gene Family Members in Moso Bamboo (Phyllostachys edulis)

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