Calcineurin Targets Involved in Stress Survival and Fungal Virulence.
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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https://hdl.handle.net/10161/13053Published Version (Please cite this version)
10.1371/journal.ppat.1005873Publication 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
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
Martin Arthur Moseley III
Adjunct Professor in the Department of Cell Biology
Erik James Soderblom
Associate Research Professor of Cell Biology
Director, Proteomics and Metabolomics Core Facility
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