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Genetics

Title:		"Dissecting the Roles of the Calcineurin Pathway in Unisexual Reproduction, Stress Responses, and Virulence in Cryptococcus deneoformans"
Author(s):		Fu C; Donadio N; Cardenas ME; Heitman J;
Address:		"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710 carde004@duke.edu heitm001@duke.edu"
Journal Title:		Genetics
Year:		2018
Volume:		20171212
Issue:		2
Page Number:		639 - 653
DOI:		10.1534/genetics.117.300422
ISSN/ISBN:		1943-2631 (Electronic) 0016-6731 (Print) 0016-6731 (Linking)
Abstract:		"The Ca(2+)/calmodulin-dependent protein phosphatase calcineurin orchestrates sexual reproduction, stress responses, and virulence via branched downstream pathways in the opportunistic human fungal pathogen Cryptococcus neoformans The calcineurin-binding protein Cbp1, the calcineurin temperature suppressor Cts1, the calcineurin-responsive zinc finger transcription factor Crz1, and the calcineurin targets Pbp1, Tif3, and Puf4, all function downstream of calcineurin to orchestrate distinct cellular processes. To elucidate how the calcineurin pathway regulatory network governs unisexual reproduction, stress responses, and virulence, we have analyzed the self-filamentous C. deneoformans strain, XL280alpha, and generated double mutants of these calcineurin downstream genes. We demonstrated that calcineurin governs unisexual reproduction at different sexual developmental stages, in which the initiation of the yeast-hyphal morphological transition is independent of Crz1, whereas the sporulation process is dependent on Crz1. Calcineurin-dependent unisexual reproduction is independent of the pheromone response pathway. Crz1 synergistically interacts with different calcineurin downstream targets in responding to ER, high-calcium, and cell wall stresses. We observed a widespread synergy suggesting that these proteins function in complex branched pathways downstream of calcineurin with some functional redundancy, which may allow efficient signaling network rewiring within the pathway for prompt adaptation to changing environments. Finally, we showed that deletion of PBP1 or TIF3 in the cna1?Os mutant background conferred a modest level of growth tolerance at 37 degrees , but that the cna1?Os pbp1?Os and cna1?Os tif3?Os double mutants were both avirulent, suggesting that calcineurin may control virulence via mechanisms beyond thermotolerance"
Keywords:		"Calcineurin/genetics/*metabolism Cryptococcosis/microbiology Cryptococcus/*physiology Environment Models, Molecular Mutation Pheromones/metabolism *Reproduction *Signal Transduction *Stress, Physiological Transcription Factors/metabolism Virulence Cryptoc;"
Notes:		"MedlineFu, Ci Donadio, Nicholas Cardenas, Maria E Heitman, Joseph eng R01 AI050113/AI/NIAID NIH HHS/ R01 CA154499/CA/NCI NIH HHS/ R37 AI039115/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural 2017/12/14 Genetics. 2018 Feb; 208(2):639-653. doi: 10.1534/genetics.117.300422. Epub 2017 Dec 12"