Abstract
AP-1-like transcription factors play evolutionarily conserved roles as redox sensors in eukaryotic oxidative stress responses. In this study, we aimed to elucidate the regulatory mechanism of an atypical yeast AP-1-like protein, Yap1, in the stress response and virulence of Cryptococcus neoformansYAP1 expression was induced and involved not only by oxidative stresses, such as H2O2 and diamide, but also by other environmental stresses, such as osmotic and membrane-destabilizing stresses. Yap1 was distributed throughout both the cytoplasm and the nucleus under basal conditions and more enriched within the nucleus in response to diamide but not to other stresses. Deletion of the C-terminal cysteine-rich domain (c-CRD), where the nuclear export signal resides, increased nuclear enrichment of Yap1 under basal conditions and altered resistance to oxidative stresses but did not affect the role of Yap1 in other stress responses and cellular functions. As a potential upstream regulator of Yap1, we discovered that Mpk1 is positively involved, but Hog1 is mostly dispensable. Pleiotropic roles for Yap1 in diverse biological processes were supported by transcriptome data showing that 162 genes are differentially regulated by Yap1, with further analysis revealing that Yap1 promotes cellular resistance to toxic cellular metabolites produced during glycolysis, such as methylglyoxal. Finally, we demonstrated that Yap1 plays a minor role in the survival of C. neoformans within hosts.IMPORTANCE The human meningitis fungal pathogen, Cryptococcus neoformans, contains the atypical yeast AP-1-like protein Yap1. Yap1 lacks an N-terminal cysteine-rich domain (n-CRD), which is present in other fungal Yap1 orthologs, but has a C-terminal cysteine-rich domain (c-CRD). However, the role of c-CRD and its regulatory mechanism remain unknown. Here, we report that Yap1 is transcriptionally regulated in response to oxidative, osmotic, and membrane-destabilizing stresses partly in an Mpk1-dependent manner, supporting its role in stress resistance. The c-CRD domain contributed to the role of Yap1 only in resistance to certain oxidative stresses and azole drugs but not in other cellular functions. Yap1 has a minor role in the survival of C. neoformans in a murine model of systemic cryptococcosis.
Highlights
AP-1-like transcription factors play evolutionarily conserved roles as redox sensors in eukaryotic oxidative stress responses
We showed that YAP1 and ATF1 expression was more highly induced by H2O2 in atf1Δ and yap1Δ mutants, respectively (Fig. 5), the yap1Δ
We addressed whether Yap1 and Atf1 play synergistic roles in C. neoformans virulence
Summary
AP-1-like transcription factors play evolutionarily conserved roles as redox sensors in eukaryotic oxidative stress responses. Deletion of the C-terminal cysteine-rich domain (c-CRD), where the nuclear export signal resides, increased nuclear enrichment of Yap under basal conditions and altered resistance to oxidative stresses but did not affect the role of Yap in other stress responses and cellular functions. We report that Yap is transcriptionally regulated in response to oxidative, osmotic, and membrane-destabilizing stresses partly in an Mpk1-dependent manner, supporting its role in stress resistance. Sensing, responding, and adapting to a myriad of environmental stresses are key abilities for all living organisms to survive in their biological niches [1, 2] These capabilities are important for infectious microbes that encounter dramatic changes in external conditions during colonization and proliferation within a host. In C. neoformans, several signaling pathways are involved in the oxidative stress defense [1] These include two mitogen-activated protein kinases (MAPKs), Hog and Mpk. Our recent systematic functional profiling of 155 TFs in C. neoformans revealed that 95 of them are positively or negatively involved in oxidative stress responses [22], suggesting that the pathogen employs diverse classes of TFs to counteract such stresses
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