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https://doi.org/10.1371/journal.ppat.1004630
Title: | Cell Cycle-Independent Phospho-Regulation of Fkh2 during Hyphal Growth Regulates Candida albicans Pathogenesis | Authors: | Greig J.A. Sudbery I.M. Richardson J.P. Naglik J.R. Wang Y. Sudbery P.E. |
Keywords: | cell wall biosynthesis kinase 1 chromatin modifier Pob3 cyclin dependent kinase 28 cytokine forkhead transcription factor forkhead transcription factor 2 lactate dehydrogenase peptides and proteins transcriptome unclassified drug cell cycle protein cyclin dependent kinase forkhead transcription factor fungal protein Article biofilm Candida albicans cell cycle progression cell damage down regulation fungus growth gel electrophoresis gene expression genetic transcription host parasite interaction human human cell immune response mass spectrometry microarray analysis microscopy mutational analysis nonhuman pathogenesis plasmid polymerase chain reaction protein analysis protein phosphorylation protein processing RNA isolation Western blotting Candida albicans cell cycle fungus hyphae gene expression profiling gene expression regulation genetics growth, development and aging host pathogen interaction metabolism pathogenicity phosphorylation physiology Candida albicans Candida albicans Cell Cycle Cell Cycle Proteins Cyclin-Dependent Kinases Forkhead Transcription Factors Fungal Proteins Gene Expression Profiling Gene Expression Regulation, Fungal Host-Pathogen Interactions Hyphae Microarray Analysis Phosphorylation Protein Processing, Post-Translational |
Issue Date: | 2015 | Citation: | Greig J.A., Sudbery I.M., Richardson J.P., Naglik J.R., Wang Y., Sudbery P.E. (2015). Cell Cycle-Independent Phospho-Regulation of Fkh2 during Hyphal Growth Regulates Candida albicans Pathogenesis. PLoS Pathogens 11 (1) : 1-31. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1004630 | Rights: | Attribution 4.0 International | Abstract: | The opportunistic human fungal pathogen, Candida albicans, undergoes morphological and transcriptional adaptation in the switch from commensalism to pathogenicity. Although previous gene-knockout studies have identified many factors involved in this transformation, it remains unclear how these factors are regulated to coordinate the switch. Investigating morphogenetic control by post-translational phosphorylation has generated important regulatory insights into this process, especially focusing on coordinated control by the cyclin-dependent kinase Cdc28. Here we have identified the Fkh2 transcription factor as a regulatory target of both Cdc28 and the cell wall biosynthesis kinase Cbk1, in a role distinct from its conserved function in cell cycle progression. In stationary phase yeast cells 2D gel electrophoresis shows that there is a diverse pool of Fkh2 phospho-isoforms. For a short window on hyphal induction, far before START in the cell cycle, the phosphorylation profile is transformed before reverting to the yeast profile. This transformation does not occur when stationary phase cells are reinoculated into fresh medium supporting yeast growth. Mass spectrometry and mutational analyses identified residues phosphorylated by Cdc28 and Cbk1. Substitution of these residues with non-phosphorylatable alanine altered the yeast phosphorylation profile and abrogated the characteristic transformation to the hyphal profile. Transcript profiling of the phosphorylation site mutant revealed that the hyphal phosphorylation profile is required for the expression of genes involved in pathogenesis, host interaction and biofilm formation. We confirmed that these changes in gene expression resulted in corresponding defects in pathogenic processes. Furthermore, we identified that Fkh2 interacts with the chromatin modifier Pob3 in a phosphorylation-dependent manner, thereby providing a possible mechanism by which the phosphorylation of Fkh2 regulates its specificity. Thus, we have discovered a novel cell cycle-independent phospho-regulatory event that subverts a key component of the cell cycle machinery to a role in the switch from commensalism to pathogenicity. ? 2015 Greig et al. | Source Title: | PLoS Pathogens | URI: | https://scholarbank.nus.edu.sg/handle/10635/161939 | ISSN: | 15537366 | DOI: | 10.1371/journal.ppat.1004630 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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