Dissecting the Roles of the Calcineurin Pathway in Unisexual Reproduction, Stress Responses, and Virulence in Cryptococcus deneoformans

Genetics: A Periodical Record of Investigations Bearing on Heredity and Variation

article

Ci Fu¹  Nicholas Donadio¹  Maria E. Cardenas¹  Joseph Heitman¹ 

[1] Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710

关键词: calcineurin;    Cryptococcus deneoformans;    genetic interactions;    unisexual reproduction;    stress response;    virulence;   

DOI  :  10.1534/genetics.117.300422

学科分类：医学（综合）

来源: Genetics Society of America

【 摘 要 】

The Ca²⁺/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, XL280α, 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 ∆ mutant background conferred a modest level of growth tolerance at 37°, but that the cna1 ∆ pbp1 ∆ and cna1 ∆ tif3 ∆ double mutants were both avirulent, suggesting that calcineurin may control virulence via mechanisms beyond thermotolerance.

【 授权许可】

CC BY