SUMOylation of Wor1 by a novel SUMO E3 ligase controls cell fate in Candida albicans

Candida albicans is the most common human fungal pathogen, yet is a normal commensal resident of the human gut. CO2 levels in the gut are much higher than in air, and it is known that elevated CO2 concentration promotes C. albicans cells to undergo a phenotypic switch from white to opaque phase. Wor1, the master regulator of opaque cell formation, is required for both the white to opaque transition and opaque maintenance. To elucidate the regulatory mechanism of Wor1, we set out to identify Wor1-interacting proteins using a yeast two-hybrid screen. A SUMO E3 ligase named Wos1 (Wor1 SUMO-ligase 1) was identified to interact with Wor1 and regulate Wor1 SUMOylation. WOS1 expression is upregulated in response to high CO2, and the induction by CO2 is dependent on the transcription factor Flo8. Under high CO2 conditions, Wos1 is required for the white to opaque switch and acts downstream of Flo8. At atmospheric CO2 levels, overexpression of Wos1 enhances Wor1 SUMOylation and promotes the white to opaque switch. Wor1 is found to be SUMOylated at lysine 385, and loss of this mark by point mutation leads to a defect in CO2-mediated opaque cell induction. Together, our genetic and biological data show that Wos1-mediated Wor1 SUMOylation contributes to the regulation of CO2-induced white to opaque switching as well as heritable maintenance of the opaque cell type.