Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

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 neo...

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Autores principales:	Yee-Seul So, Shinae Maeng, Dong-Hoon Yang, Hyelim Kim, Kyung-Tae Lee, Seong-Ryong Yu, Jennifer L. Tenor, Vinay K. Giri, Dena L. Toffaletti, Samantha Arras, James A. Fraser, John R. Perfect, Yong-Sun Bahn
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	AP-1-like transcription factor C. neoformans Mpk1 Yap1 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a892d0833c1e4cecbf0b40be9220c7b9
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spelling	oai:doaj.org-article:a892d0833c1e4cecbf0b40be9220c7b92021-11-15T15:22:24ZRegulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>10.1128/mSphere.00785-192379-5042https://doaj.org/article/a892d0833c1e4cecbf0b40be9220c7b92019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00785-19https://doaj.org/toc/2379-5042ABSTRACT 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.Yee-Seul SoShinae MaengDong-Hoon YangHyelim KimKyung-Tae LeeSeong-Ryong YuJennifer L. TenorVinay K. GiriDena L. ToffalettiSamantha ArrasJames A. FraserJohn R. PerfectYong-Sun BahnAmerican Society for MicrobiologyarticleAP-1-like transcription factorC. neoformansMpk1Yap1MicrobiologyQR1-502ENmSphere, Vol 4, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	AP-1-like transcription factor C. neoformans Mpk1 Yap1 Microbiology QR1-502
spellingShingle	AP-1-like transcription factor C. neoformans Mpk1 Yap1 Microbiology QR1-502 Yee-Seul So Shinae Maeng Dong-Hoon Yang Hyelim Kim Kyung-Tae Lee Seong-Ryong Yu Jennifer L. Tenor Vinay K. Giri Dena L. Toffaletti Samantha Arras James A. Fraser John R. Perfect Yong-Sun Bahn Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
description	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 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.
format	article
author	Yee-Seul So Shinae Maeng Dong-Hoon Yang Hyelim Kim Kyung-Tae Lee Seong-Ryong Yu Jennifer L. Tenor Vinay K. Giri Dena L. Toffaletti Samantha Arras James A. Fraser John R. Perfect Yong-Sun Bahn
author_facet	Yee-Seul So Shinae Maeng Dong-Hoon Yang Hyelim Kim Kyung-Tae Lee Seong-Ryong Yu Jennifer L. Tenor Vinay K. Giri Dena L. Toffaletti Samantha Arras James A. Fraser John R. Perfect Yong-Sun Bahn
author_sort	Yee-Seul So
title	Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_short	Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full	Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_fullStr	Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_full_unstemmed	Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>
title_sort	regulatory mechanism of the atypical ap-1-like transcription factor yap1 in <named-content content-type="genus-species">cryptococcus neoformans</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/a892d0833c1e4cecbf0b40be9220c7b9
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Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in <named-content content-type="genus-species">Cryptococcus neoformans</named-content>

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