The human pathogen Cryptococcus neoformans, which causes life-threatening meningoencephalitis in immunocompromised individuals, normally faces diverse stresses in the human host. Here, we report that a novel, basic, leucine-zipper (bZIP) protein, designated Gsb1 (general stress-related bZIP protein 1), is required for its normal growth and diverse stress responses. C. neoformans gsb1Δ mutants grew slowly even under non-stressed conditions and showed increased sensitivity to high or low temperatures. The hypersensitivity of gsb1Δ to oxidative and nitrosative stresses was reversed by addition of a ROS scavenger. RNA-Seq analysis during normal growth revealed increased expression of a number of genes involved in mitochondrial respiration and cell cycle, but decreased expression of several genes involved in the mating-pheromone-responsive MAPK signaling pathway. Accordingly, gsb1Δ showed defective mating and abnormal cell-cycle progression. Reflecting these pleiotropic phenotypes, gsb1Δ exhibited attenuated virulence in a murine model of cryptococcosis. Moreover, RNA-Seq analysis under oxidative stress revealed that several genes involved in ROS defense, cell-wall remodeling, and protein glycosylation were highly induced in the wild-type strain but not in gsb1Δ. Gsb1 localized exclusively in the nucleus in response to oxidative stress. In conclusion, Gsb1 is a key transcription factor modulating growth, stress responses, differentiation, and virulence in C. neoformans.
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (Grant No. NRF-2016R1D1A1B03934249) from the Korean Ministry of Ministry of Science, ICT and Future Planning and by the Strategic Initiative for Microbiomes in Agriculture and Food from the Korean Ministry of Agriculture, Food, and Rural Affairs (Grant No. 914007-4) to H. A. K. This work was partly supported by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food, and Rural Affairs (Grant No. 916006-2) to Y.-S. B. We are grateful to Dr. Yin-Won Lee for providing inspiring comments and encouragement.
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