Copper-responsive transcriptional regulation in candida albicans

The copper-containing protein superoxide dismutase is required for the virulence of C. albicans in a mouse model. Previous work in our laboratory has shown that copper uptake and regulation in C. albicans has some similarities to Saccharomyces cerevisiae, including the activation of the copper transporter gene CaCTR1 in low copper conditions by the transcription factor CaMac1p. However, further analysis in this study has demonstrated that the actual mechanism of regulation by CaMac1p is different from that of S. cerevisiae Mac1p. This thesis demonstrates for the first time that the CaMAC1 gene is transcriptionally autoregulated in a copper-dependent manner. This is in contrast to the S. cerevisiae MAC1 homologue, which is constitutively transcribed. The presence of one binding site for CaMac1p in the promoters of CaCTR1, CaMAC1 and the ferric/cupric reductase gene CaFRE7 is sufficient for copper-responsive regulation. In contrast, two promoter elements are essential for normal levels of copper-dependent activation by S. cerevisiae Mac1p. CaMac1p is also involved in the regulation of the iron-responsive transcriptional repressor gene SFU1 and the alternative oxidase gene AOX2. This work describes key features of the copper uptake system in the human pathogen C. albicans that distinguishes it from similar processes in the model yeast S. cerevisiae. Transcriptional autoregulation of the CaMAC1 gene could enable C. albicans to respond more precisely to environmental changes, conferring an adaptation to the human host that may be an advantage in the disease process.