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Calcineurin Targets Involved in Stress Survival and Fungal Virulence.

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Date
2016-09
Authors
Park, Hee-Soo
Chow, Eve WL
Fu, Ci
Soderblom, Erik J
Moseley, M Arthur
Heitman, Joseph
Cardenas, Maria E
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Abstract
Calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen Cryptococcus neoformans. Calcineurin is activated by increased Ca2+ levels caused by stress, and transduces signals by dephosphorylating protein substrates. Herein, we identified and characterized calcineurin substrates in C. neoformans by employing phosphoproteomic TiO2 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.
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Journal article
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https://hdl.handle.net/10161/13053
Published Version (Please cite this version)
10.1371/journal.ppat.1005873
Publication Info
Park, Hee-Soo; Chow, Eve WL; Fu, Ci; Soderblom, Erik J; Moseley, M Arthur; Heitman, Joseph; & Cardenas, Maria E (2016). Calcineurin Targets Involved in Stress Survival and Fungal Virulence. PLoS Pathog, 12(9). pp. e1005873. 10.1371/journal.ppat.1005873. Retrieved from https://hdl.handle.net/10161/13053.
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Scholars@Duke

Heitman

Joseph Heitman

Chair, Department of Molecular Genetics and Microbiology
Joseph Heitman was an undergraduate at the University of Chicago (1980-1984), graduating from the BS-MS program with dual degrees in chemistry and biochemistry with general and special honors. He then matriculated as an MD-PhD student at Cornell and Rockefeller Universities and worked with Peter Model and Norton Zinder on how restriction enzymes recognize specific DNA sequences and how bacteria respond to and repair DNA breaks and nicks. Dr. Heitman moved as an EMBO long-term fellow to the Bi
Moseley

Martin Arthur Moseley III

Adjunct Professor in the Department of Cell Biology
Soderblom

Erik James Soderblom

Associate Research Professor of Cell Biology
Director, Proteomics and Metabolomics Core Facility
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