title: Pho85, Pcl1, and Hms1 signaling governs Candida albicans morphogenesis induced by high temperature or Hsp90 compromise.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shapiro
authors.forename: Adnane
authors.initials: A
authors.lastname: Sellam
authors.forename: Faiza
authors.initials: F
authors.lastname: Tebbji
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whiteway
authors.forename: Andre
authors.initials: A
authors.lastname: Nantel
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cowen
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002176:Candida albicans / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism* / Q000472:pathogenicity; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004843:Epistasis, Genetic; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005800:Genes, Fungal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009024:Morphogenesis; D009036:Moths / Q000382:microbiology; D015398:Signal Transduction; D013696:Temperature; D014774:Virulence / Q000235:genetics / Q000502:physiology
chemical_list: D016227:Benzoquinones; D016213:Cyclins; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018844:Cyclin-Dependent Kinases; C001277:geldanamycin