A transcription factor regulatory cascade controls secreted aspartic protease expression in Candida albicans

Secreted aspartic proteases (Saps) contribute to the virulence of Candida albicans, a major fungal pathogen of humans. One function of the Saps, which is specifically mediated by the Sap2p isoenzyme, is the degradation of proteins for use as a nitrogen source. The utilization of alternative nitrogen sources in fungi is controlled by GATA transcription factors and we found that C. albicans mutants lacking the GATA transcription factors Gln3p and Gat1p were unable to grow in a medium containing bovine serum albumin (BSA) as the sole nitrogen source. The growth defect was mainly caused by the inability of gln3Deltagat1Delta mutants to express the SAP2 gene, as SAP2 expression from the constitutive ADH1 promoter restored the ability of the mutants to grow on BSA. Expression of STP1, which encodes a transcription factor that is required for SAP2 induction in the presence of proteins, was regulated by Gln3p and Gat1p, and forced expression of STP1 from a tetracycline-inducible promoter bypassed the requirement of the GATA transcription factors for growth of C. albicans on proteins. SAP2 is repressed when preferred nitrogen sources are available and this nitrogen catabolite repression of SAP2 was correlated with downregulation of STP1 in the presence of high concentrations of ammonium, glutamine or urea. Tetracycline-induced STP1 expression abolished nitrogen catabolite repression of SAP2, demonstrating that the control of STP1 expression levels by the GATA transcription factors is a key aspect of both positive and negative regulation of SAP2 expression. Therefore, secreted aspartic protease expression, a long-known virulence attribute of C. albicans, is controlled by a regulatory cascade in which the general regulators Gln3p and Gat1p control the expression of the transcription factor Stp1p, which in turn mediates SAP2 expression.