Cell wall integrity is dependent on the <i>PKC1</i> signal transduction pathway in <i>Cryptococcus neoformans</i>

Gerik, Kimberly J.; Donlin, Maureen J.; Soto, Carlos E.; Banks, Annette M.; Banks, Isaac R.; Maligie, Marybeth A.; Selitrennikoff, Claude P.; Lodge, Jennifer K.

doi:10.1111/j.1365-2958.2005.04843.x

Cited by 139 publications

(187 citation statements)

References 46 publications

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“…A PUF family member in C. neoformans, Puf4, plays a role in host temperature adaptation, as a puf4⌬ mutant exhibits a temperature-sensitive growth phenotype and cell integrity defects (10). This may suggest that Puf4 and Ccr4 cooperate to promote host temperature adaptation through regulation of mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

et al. 2011

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Adaptation to host temperature is a prerequisite for any pathogen capable of causing deep infection in humans. Our previous studies demonstrated that a Cryptococcus neoformans ccr4⌬ mutant lacking the major deadenylase involved in regulated mRNA decay was defective in host temperature adaptation and therefore virulence. In this study, the ccr4⌬ mutant was found to exhibit characteristics of chronic unfolded-protein response (UPR) engagement in both the gene expression profile and phenotype. We demonstrate that host temperature adaptation in C. neoformans is accompanied by transient induction of the endoplasmic reticulum (ER) stress response and that Ccr4-dependent posttranscriptional gene regulation contributes to resolution of ER stress during host temperature adaptation.The pathogenic fungus Cryptococcus neoformans is one of two species of cryptococci commonly associated with infection in humans (2, 6). Unifying characteristics of the pathogenic cryptococci include the production of a polysaccharide capsule, the ability to form melanin pigments through the activity of the multicopper oxidase laccase, and the ability to adapt to and thrive at mammalian host temperature. Adaptation of C. neoformans to the host temperature is accompanied by major changes in gene expression as measured by microarray analysis and serial analysis of gene expression (SAGE) (5,19,29). This modulation of gene expression likely requires alterations in mRNA synthesis rates through activation of transcriptional transactivators and repressors, as well as alterations in chromatin structure. In addition to mRNA synthesis, our previous studies of a C. neoformans ccr4⌬ mutant lacking the major mRNA deadenylase involved in regulated mRNA turnover suggest a role for posttranscriptional regulation of gene expression in C. neoformans host temperature adaptation (24).Destabilization of specific transcripts in response to stress is highly conserved. In the model yeast Saccharomyces cerevisiae, deletion of CCR4 results in stabilization of transcripts encoding distinct functional classes (ribosome biogenesis, translation initiation, and tRNA synthesis) in response to temperature stress (13). In mammalian cells, subsets of transcripts were destabilized in response to heat shock, and induction of endoplasmic reticulum (ER) stress by treatment with tunicamycin or potentiation of ER calcium release by thapsigargin treatment triggered destabilization of a subset of mRNAs in which are included several transcripts encoding ribosomal proteins (8). This suggests that in response to heat shock and ER stress, distinct pools of transcripts representing specific cellular processes are targeted for degradation.The conserved ER stress response involves engagement of the unfolded-protein response (UPR) and the ER-associated degradation (ERAD) pathway (18). The UPR serves to retool the ER for enhanced protein folding, and ERAD serves to remove unfolded proteins from the ER lumen and shunt them into a degradative pathway. Microarray analyses performed in S. cerevisiae ...

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Section: Discussionmentioning

confidence: 99%

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

et al. 2011

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“…An overlap PCR gene deletion technology (supplemental material) (13,19) was used to generate gene-specific deletion cassettes of CHS1, CHS3, CHS4, CHS5, CHS6, CHS7, CHS8, and CSR2 that included a nourseothricin cassette (31) and a hygromycin cassette (20) for CHS2, CSR1, and CSR3. This resulted in the deletion of greater than 95% of CHS1, greater than 81% of CHS2, greater than 99% of CHS3, greater than 97% of CHS4, greater than 98% of CHS5, greater than 96% of CHS6, greater than 89% of CHS7, greater than 95% of CHS8, 54% of CSR1, greater than 90% of CSR2, and 19% of CSR3.…”

Section: Methodsmentioning

confidence: 99%

A Chitin Synthase and Its Regulator Protein Are Critical for Chitosan Production and Growth of the Fungal Pathogen Cryptococcus neoformans

Banks¹,

et al. 2005

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Chitin is an essential component of the cell wall of many fungi. Chitin also can be enzymatically deacetylated to chitosan, a more flexible and soluble polymer. Cryptococcus neoformans is a fungal pathogen that causes cryptococcal meningoencephalitis, particularly in immunocompromised patients. In this work, we show that both chitin and chitosan are present in the cell wall of vegetatively growing C. neoformans yeast cells and that the levels of both rise dramatically as cells grow to higher density in liquid culture. C. neoformans has eight putative chitin synthases, and strains with any one chitin synthase deleted are viable at 30°C. In addition, C. neoformans genes encode three putative regulator proteins, which are homologs of Saccharomyces cerevisiae Skt5p. None of these three is essential for viability. However, one of the chitin synthases (Chs3) and one of the regulators (Csr2) are important for growth. Cells with deletions in either CHS3 or CSR2 have several shared phenotypes, including sensitivity to growth at 37°C. The similarity of their phenotypes also suggests that Csr2 specifically regulates chitin synthesis by Chs3. Lastly, both chs3⌬ and the csr2⌬ mutants are defective in chitosan production, predicting that Chs3-Csr2 complex with chitin deacetylases for conversion of chitin to chitosan. These data suggest that chitin synthesis could be an excellent antifungal target.

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“…Exposure of fungi to sublethal concentrations of cell wall-targeting antifungals, triggers the cell wall integrity (CWI) signaling pathway in both yeasts and filamentous fungi (Levin 2005;Gerik et al 2005;Damveld et al 2005b). Activation of the pathway results in the induced expression of several genes involved in cell wall synthesis and remodeling.…”

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confidence: 99%

A Novel Screening Method for Cell Wall Mutants in Aspergillus niger Identifies UDP-Galactopyranose Mutase as an Important Protein in Fungal Cell Wall Biosynthesis

et al. 2008

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To identify cell wall biosynthetic genes in filamentous fungi and thus potential targets for the discovery of new antifungals, we developed a novel screening method for cell wall mutants. It is based on our earlier observation that the Aspergillus niger agsA gene, which encodes a putative a-glucan synthase, is strongly induced in response to cell wall stress. By placing the agsA promoter region in front of a selectable marker, the acetamidase (amdS) gene of A. nidulans, we reasoned that cell wall mutants with a constitutively active cell wall stress response pathway could be identified by selecting mutants for growth on acetamide as the sole nitrogen source. For the genetic screen, a strain was constructed that contained two reporter genes controlled by the same promoter: the metabolic reporter gene PagsA-amdS and PagsA-H2B-GFP, which encodes a GFP-tagged nuclear protein. The primary screen yielded 161 mutants that were subjected to various cell wall-related secondary screens. Four calcofluor white-hypersensitive, osmotic-remediable thermosensitive mutants were selected for complementation analysis. Three mutants were complemented by the same gene, which encoded a protein with high sequence identity with eukaryotic UDP-galactopyranose mutases (UgmA). Our results indicate that galactofuranose formation is important for fungal cell wall biosynthesis and represents an attractive target for the development of antifungals.

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Cell wall integrity is dependent on the PKC1 signal transduction pathway in Cryptococcus neoformans

Cited by 139 publications

References 46 publications

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

A Chitin Synthase and Its Regulator Protein Are Critical for Chitosan Production and Growth of the Fungal Pathogen Cryptococcus neoformans

A Novel Screening Method for Cell Wall Mutants in Aspergillus niger Identifies UDP-Galactopyranose Mutase as an Important Protein in Fungal Cell Wall Biosynthesis

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