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Calcineurin Targets Involved in Stress Survival and Fungal Virulence
Calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen Cryptococcus neoformans. Calcineurin is activated by increased Ca(2+) levels caused by stress, and transduces signals by dephosphorylating protein substrates. Herein, we identified and characteriz...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017699/ https://www.ncbi.nlm.nih.gov/pubmed/27611567 http://dx.doi.org/10.1371/journal.ppat.1005873 |
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author | Park, Hee-Soo Chow, Eve W. L. Fu, Ci Soderblom, Erik J. Moseley, M. Arthur Heitman, Joseph Cardenas, Maria E. |
author_facet | Park, Hee-Soo Chow, Eve W. L. Fu, Ci Soderblom, Erik J. Moseley, M. Arthur Heitman, Joseph Cardenas, Maria E. |
author_sort | Park, Hee-Soo |
collection | PubMed |
description | Calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen Cryptococcus neoformans. Calcineurin is activated by increased Ca(2+) levels caused by stress, and transduces signals by dephosphorylating protein substrates. Herein, we identified and characterized calcineurin substrates in C. neoformans by employing phosphoproteomic TiO(2) enrichment and quantitative mass spectrometry. The identified targets include the transactivator Crz1 as well as novel substrates whose functions are linked to P-bodies/stress granules (PBs/SGs) and mRNA translation and decay, such as Pbp1 and Puf4. We show that Crz1 is a bona fide calcineurin substrate, and Crz1 localization and transcriptional activity are controlled by calcineurin. We previously demonstrated that thermal and other stresses trigger calcineurin localization to PBs/SGs. Several calcineurin targets localized to PBs/SGs, including Puf4 and Pbp1, contribute to stress resistance and virulence individually or in conjunction with Crz1. Moreover, Pbp1 is also required for sexual development. Genetic epistasis analysis revealed that Crz1 and the novel targets Lhp1, Puf4, and Pbp1 function in a branched calcineurin pathway that orchestrates stress survival and virulence. These findings support a model whereby calcineurin controls stress and virulence, at the transcriptional level via Crz1, and post-transcriptionally by localizing to PBs/SGs and acting on targets involved in mRNA metabolism. The calcineurin targets identified in this study share little overlap with known calcineurin substrates, with the exception of Crz1. In particular, the mRNA binding proteins and PBs/SGs residents comprise a cohort of novel calcineurin targets that have not been previously linked to calcineurin in mammals or in Saccharomyces cerevisiae. This study suggests either extensive evolutionary rewiring of the calcineurin pathway, or alternatively that these novel calcineurin targets have yet to be characterized as calcineurin targets in other organisms. These findings further highlight C. neoformans as an outstanding model to define calcineurin-responsive virulence networks as targets for antifungal therapy. |
format | Online Article Text |
id | pubmed-5017699 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50176992016-09-27 Calcineurin Targets Involved in Stress Survival and Fungal Virulence Park, Hee-Soo Chow, Eve W. L. Fu, Ci Soderblom, Erik J. Moseley, M. Arthur Heitman, Joseph Cardenas, Maria E. PLoS Pathog Research Article Calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen Cryptococcus neoformans. Calcineurin is activated by increased Ca(2+) levels caused by stress, and transduces signals by dephosphorylating protein substrates. Herein, we identified and characterized calcineurin substrates in C. neoformans by employing phosphoproteomic TiO(2) enrichment and quantitative mass spectrometry. The identified targets include the transactivator Crz1 as well as novel substrates whose functions are linked to P-bodies/stress granules (PBs/SGs) and mRNA translation and decay, such as Pbp1 and Puf4. We show that Crz1 is a bona fide calcineurin substrate, and Crz1 localization and transcriptional activity are controlled by calcineurin. We previously demonstrated that thermal and other stresses trigger calcineurin localization to PBs/SGs. Several calcineurin targets localized to PBs/SGs, including Puf4 and Pbp1, contribute to stress resistance and virulence individually or in conjunction with Crz1. Moreover, Pbp1 is also required for sexual development. Genetic epistasis analysis revealed that Crz1 and the novel targets Lhp1, Puf4, and Pbp1 function in a branched calcineurin pathway that orchestrates stress survival and virulence. These findings support a model whereby calcineurin controls stress and virulence, at the transcriptional level via Crz1, and post-transcriptionally by localizing to PBs/SGs and acting on targets involved in mRNA metabolism. The calcineurin targets identified in this study share little overlap with known calcineurin substrates, with the exception of Crz1. In particular, the mRNA binding proteins and PBs/SGs residents comprise a cohort of novel calcineurin targets that have not been previously linked to calcineurin in mammals or in Saccharomyces cerevisiae. This study suggests either extensive evolutionary rewiring of the calcineurin pathway, or alternatively that these novel calcineurin targets have yet to be characterized as calcineurin targets in other organisms. These findings further highlight C. neoformans as an outstanding model to define calcineurin-responsive virulence networks as targets for antifungal therapy. Public Library of Science 2016-09-09 /pmc/articles/PMC5017699/ /pubmed/27611567 http://dx.doi.org/10.1371/journal.ppat.1005873 Text en © 2016 Park et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Park, Hee-Soo Chow, Eve W. L. Fu, Ci Soderblom, Erik J. Moseley, M. Arthur Heitman, Joseph Cardenas, Maria E. Calcineurin Targets Involved in Stress Survival and Fungal Virulence |
title | Calcineurin Targets Involved in Stress Survival and Fungal Virulence |
title_full | Calcineurin Targets Involved in Stress Survival and Fungal Virulence |
title_fullStr | Calcineurin Targets Involved in Stress Survival and Fungal Virulence |
title_full_unstemmed | Calcineurin Targets Involved in Stress Survival and Fungal Virulence |
title_short | Calcineurin Targets Involved in Stress Survival and Fungal Virulence |
title_sort | calcineurin targets involved in stress survival and fungal virulence |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017699/ https://www.ncbi.nlm.nih.gov/pubmed/27611567 http://dx.doi.org/10.1371/journal.ppat.1005873 |
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