BACKGROUND: Temperature exerts powerful control over development and virulence of diverse pathogens. In the leading human fungal pathogen, Candida albicans, temperature governs morphogenesis, a key virulence trait. Many cues that induce the yeast to filament transition are contingent on a minimum of 37°C, whereas further elevation to 39°C serves as an independent inducer. The molecular chaperone Hsp90 is a key regulator of C. albicans temperature-dependent morphogenesis. Compromise of Hsp90 function genetically, pharmacologically, or by elevated temperature induces filamentation in a manner that depends on protein kinase A signaling but is independent of the terminal transcription factor, Efg1. RESULTS: Here, we establish that despite morphological and regulatory differences, inhibition of Hsp90 induces a transcriptional profile similar to that induced by other filamentation cues and does so independently of Efg1. Further, we identify Hms1 as a transcriptional regulator required for morphogenesis induced by elevated temperature or Hsp90 compromise. Hms1 functions downstream of the cyclin Pcl1 and the cyclin-dependent kinase Pho85, both of which are required for temperature-dependent filamentation. Upon Hsp90 inhibition, Hms1 binds to DNA elements involved in filamentous growth, including UME6 and RBT5, and regulates their expression, providing a mechanism through which Pho85, Pcl1, and Hms1 govern morphogenesis. Consistent with the importance of morphogenetic flexibility for virulence, deletion of C. albicans HMS1 attenuates virulence in a metazoan model of infection. CONCLUSIONS: Thus, we establish a new mechanism through which Hsp90 orchestrates C. albicans morphogenesis, and define novel regulatory circuitry governing a temperature-dependent developmental program, with broad implications for temperature sensing and virulence of microbial pathogens. Copyright Â
BACKGROUND: Temperature exerts powerful control over development and virulence of diverse pathogens. In the leading human fungal pathogen, Candida albicans, temperature governs morphogenesis, a key virulence trait. Many cues that induce the yeast to filament transition are contingent on a minimum of 37°C, whereas further elevation to 39°C serves as an independent inducer. The molecular chaperone Hsp90 is a key regulator of C. albicans temperature-dependent morphogenesis. Compromise of Hsp90 function genetically, pharmacologically, or by elevated temperature induces filamentation in a manner that depends on protein kinase A signaling but is independent of the terminal transcription factor, Efg1. RESULTS: Here, we establish that despite morphological and regulatory differences, inhibition of Hsp90 induces a transcriptional profile similar to that induced by other filamentation cues and does so independently of Efg1. Further, we identify Hms1 as a transcriptional regulator required for morphogenesis induced by elevated temperature or Hsp90 compromise. Hms1 functions downstream of the cyclin Pcl1 and the cyclin-dependent kinase Pho85, both of which are required for temperature-dependent filamentation. Upon Hsp90 inhibition, Hms1 binds to DNA elements involved in filamentous growth, including UME6 and RBT5, and regulates their expression, providing a mechanism through which Pho85, Pcl1, and Hms1 govern morphogenesis. Consistent with the importance of morphogenetic flexibility for virulence, deletion of C. albicans HMS1 attenuates virulence in a metazoan model of infection. CONCLUSIONS: Thus, we establish a new mechanism through which Hsp90 orchestrates C. albicans morphogenesis, and define novel regulatory circuitry governing a temperature-dependent developmental program, with broad implications for temperature sensing and virulence of microbial pathogens. Copyright Â