Regulatory Mechanism of the Atypical AP-1-Like Transcription Factor Yap1 in Cryptococcus neoformans

Abstract

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.

Host-derived Reactive Nitrogen Species mediate theCryptococcus neoformansyeast-to-titan switch via fungal-derived superoxide

“…SOD2 is required for high-temperature growth and targets superoxide generated by mitochondrial Complex III [30,61] Interestingly, previous work showed that deletion of SOD1 in C. neoformans results in reduced virulence and increased sensitivity to iNOS-mediated macrophage killing [30,61]. In addition, the yap1Δ mutant exhibits reduced dissemination to the brain and slightly reduced overall virulence [59]. We demonstrate that the yap1Δ mutant fails to produce high ploidy titan cells and has a defect in titanide production, and that loss of YAP1 impairs regulation of SOD1.…”

“…The AP-1-like transcription factor Yap1 is a stress response protein induced by oxidative stress in C. neoformans, and loss of YAP1 sensitizes cells to a wide variety of oxidative stress compounds (H 2 O 2 , t-BOOH (H 2 O 2 ), diamide (O 2 -)) [59,60].…”

Unraveling Capsule Biosynthesis and Signaling Networks in Cryptococcus neoformans

“…We performed RNA sequencing (RNA-seq)-based transcriptome analysis of wild-type and bzp4 Δ, ada2 Δ, and gat201 Δ mutant strains under both basal and capsule-inducing conditions. We did not include the yap1 Δ mutant in this analysis because Yap1 appeared to mainly act upstream of Gat201, and Yap1-dependent transcriptome profiles were partly reported ( 26 ). We also decided to use LIT medium rather than FBS for the capsule-inducing condition because LIT is a better defined medium than FBS.…”

“…However, other virulence factors could contribute to the reduced virulence and/or infectivity of the ada2 Δ, yap1 Δ, and gat201 Δ mutants. Notably, all of these mutants show reduced resistance to oxidative, osmotic, and membrane stress ( 22 , 26 ). Bzp4 is positively involved in the production of two major virulence factors, melanin and capsule, but is dispensable for general stress resistance, virulence in the insect host, and murine infectivity ( 25 ).…”

“…Supporting this, the transcriptome profiles of the gat201 Δ and ada2 Δ mutants under capsule-inducing conditions were highly correlated. Yap1 is a bZIP-containing AP-1-like TF that is generally involved in oxidative stress response ( 26 ). Ada2 is a member of the Spt-Ada-Gcn5 acetyltransferase complex which regulates the transcription of stress response genes via histone acetylation, collaborating with other TFs ( 29 ).…”