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Rhb1 regulates the expression of secreted aspartic protease 2 through the TOR signaling pathway in Candida albicans.

ABSTRACT: Candida albicans is a major fungal pathogen in humans. In C. albicans, secreted aspartyl protease 2 (Sap2) is the most highly expressed secreted aspartic protease in vitro and is a virulence factor. Recent research links the small GTPase Rhb1 to C. albicans target of rapamycin (TOR) signaling in response to nitrogen availability. The results of this study show that Rhb1 is related to cell growth through the control of SAP2 expression when protein is the major nitrogen source. This process involves various components of the TOR signaling pathway, including Tor1 kinase and its downstream effectors. TOR signaling not only controls SAP2 transcription but also affects Sap2 protein levels, possibly through general amino acid control. DNA microarray analysis identifies other target genes downstream of Rhb1 in addition to SAP2. These findings provide new insight into nutrients, Rhb1-TOR signaling, and expression of C. albicans virulence factor.

SUBMITTER: Chen YT

PROVIDER: S-EPMC3272892 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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Rhb1 regulates the expression of secreted aspartic protease 2 through the TOR signaling pathway in Candida albicans.

Chen Yu-Ting YT Lin Chia-Ying CY Tsai Pei-Wen PW Yang Cheng-Yao CY Hsieh Wen-Ping WP Lan Chung-Yu CY

Eukaryotic cell 20111222 2

Candida albicans is a major fungal pathogen in humans. In C. albicans, secreted aspartyl protease 2 (Sap2) is the most highly expressed secreted aspartic protease in vitro and is a virulence factor. Recent research links the small GTPase Rhb1 to C. albicans target of rapamycin (TOR) signaling in response to nitrogen availability. The results of this study show that Rhb1 is related to cell growth through the control of SAP2 expression when protein is the major nitrogen source. This process involv ...[more]

PMID: 22194462

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Project description:Candida albicans is among the most prevalent opportunistic human fungal pathogens. The ability to mask the immunogenic polysaccharide ? (1,3)-glucan from immune detection via a layer of mannosylated proteins is a key virulence factor of C. albicans We previously reported that hyperactivation of the Cek1 mitogen-activated protein (MAP) kinase pathway promotes ? (1,3)-glucan exposure. In this communication, we report a novel upstream regulator of Cek1 activation and characterize the impact of Cek1 activity on fungal virulence. Lrg1 encodes a GTPase-activating protein (GAP) that has been suggested to inhibit the GTPase Rho1. We found that disruption of LRG1 causes Cek1 hyperactivation and ? (1,3)-glucan unmasking. However, when GTPase activation was measured for a panel of GTPases, the lrg1?? mutant exhibited increased activation of Cdc42 and Ras1 but not Rho1 or Rac1. Unmasking and Cek1 activation in the lrg1?? mutant can be blocked by inhibition of the Ste11 MAP kinase kinase kinase (MAPKKK), indicating that the lrg1?? mutant acts through the canonical Cek1 MAP kinase cascade. In order to determine how Cek1 hyperactivation specifically impacts virulence, a doxycycline-repressible hyperactive STE11?N467 allele was expressed in C. albicans In the absence of doxycycline, this allele overexpressed STE11?N467 , which induced production of proinflammatory tumor necrosis factor alpha (TNF-?) from murine macrophages. This in vitro phenotype correlates with decreased colonization and virulence in a mouse model of systemic infection. The mechanism by which Ste11?N467 causes unmasking was explored with RNA sequencing (RNA-Seq) analysis. Overexpression of Ste11?N467 caused upregulation of the Cph1 transcription factor and of a group of cell wall-modifying proteins which are predicted to impact cell wall architecture.IMPORTANCE Candida albicans is an important source of systemic infections in humans. The ability to mask the immunogenic cell wall polymer ? (1,3)-glucan from host immune surveillance contributes to fungal virulence. We previously reported that the hyperactivation of the Cek1 MAP kinase cascade promotes cell wall unmasking, thus increasing strain immunogenicity. In this study, we identified a novel regulator of the Cek1 pathway called Lrg1. Lrg1 is a predicted GTPase-activating protein (GAP) that represses Cek1 activity by downregulating the GTPase Cdc42 and its downstream MAPKKK, Ste11. Upregulation of Cek1 activity diminished fungal virulence in the mouse model of infection, and this correlates with increased cytokine responses from macrophages. We also analyzed the transcriptional profile determined during ? (1,3)-glucan exposure driven by Cek1 hyperactivation. Our report provides a model where Cek1 hyperactivation causes ? (1,3)-glucan exposure by upregulation of cell wall proteins and leads to more robust immune detection in vivo, promoting more effective clearance.

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Rhb1 regulates the expression of secreted aspartic protease 2 through the TOR signaling pathway in Candida albicans.

Publications

Rhb1 regulates the expression of secreted aspartic protease 2 through the TOR signaling pathway in Candida albicans.

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