Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in Cryptococcus neoformans
Autor: | John R. Perfect, Jennifer L. Tenor, Dena L. Toffaletti, James A. Fraser, Yee Seul So, Hyelim Kim, Seong Ryong Yu, Samantha D. M. Arras, Yong Sun Bahn, Shinae Maeng, Kyung-Tae Lee, Vinay K. Giri, Dong-Hoon Yang |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Molecular Biology and Physiology DNA Mutational Analysis 030106 microbiology lcsh:QR1-502 Oxidative phosphorylation medicine.disease_cause Microbiology c. neoformans lcsh:Microbiology Fungal Proteins Transcriptome 03 medical and health sciences Stress Physiological Gene Expression Regulation Fungal medicine mpk1 Animals yap1 Nuclear export signal Molecular Biology Gene Transcription factor Sequence Deletion Cryptococcus neoformans YAP1 Mice Inbred BALB C Microbial Viability Virulence biology ap-1-like transcription factor Gene Expression Profiling Cryptococcosis biology.organism_classification eye diseases QR1-502 Cell biology Disease Models Animal Oxidative Stress Protein Transport 030104 developmental biology Oxidative stress Transcription Factors Research Article |
Zdroj: | mSphere, Vol 4, Iss 6, p e00785-19 (2019) mSphere, Vol 4, Iss 6 (2019) mSphere |
ISSN: | 2379-5042 |
Popis: | 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. 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 neoformans. YAP1 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. |
Databáze: | OpenAIRE |
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