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Glycosylphosphatidylinositol (GPI)-anchored proteins are important for virulence of many pathogenic organisms including the human fungal pathogen,  Candida albicans . GPI biosynthesis is initiated by a multi-subunit enzyme, GPI- N- acetylglucosaminyltransferase (GPI-GnT). We showed previously that two GPI-GnT subunits, encoded by  CaGPI2  and  CaGPI19 , are mutually repressive.  CaGPI19  also co-regulates  CaERG11 , the target of azoles while  CaGPI2  controls Ras signaling and hyphal morphogenesis. Here, we investigated the role of a third subunit. We show that CaGpi15 is functionally homologous to  Saccharomyces cerevisiae  Gpi15.  CaGPI15  is a master activator of  CaGPI2  and  CaGPI19 . Hence,  CaGPI15  mutants are azole-sensitive and hypofilamentous. Altering  CaGPI19  or  CaGPI2  expression in  CaGPI15  mutant can elicit alterations in azole sensitivity via  CaERG11  expression or hyphal morphogenesis, respectively. Thus,  CaGPI2  and  CaGPI19  function downstream of  CaGPI15 . One mode of regulation is via H3 acetylation of the respective GPI-GnT gene promoters by Rtt109. Azole sensitivity of GPI-GnT mutants is also due to decreased H3 acetylation at the  CaERG11  promoter by Rtt109. Using double heterozygous mutants, we also show that  CaGPI2  and  CaGPI19  can independently activate  CaGPI15 .  CaGPI15  mutant is more susceptible to killing by macrophages and epithelial cells and has reduced ability to damage either of these cell lines relative to the wild type strain, suggesting that it is attenuated in virulence.

Modulation of azole sensitivity and filamentation by GPI15, encoding a subunit of the first GPI biosynthetic enzyme, in Candida albicans