Ras signaling activates glycosylphosphatidylinositol (GPI) anchor biosynthesis via the GPI–N-acetylglucosaminyltransferase (GPI–GnT) in Candida albicans

Abstract

The ability of to switch between yeast to hyphal form is a property that is primarily associated with the invasion and virulence of this human pathogenic fungus. Several glycosylphosphatidylinositol (GPI)-anchored proteins are expressed only during hyphal morphogenesis. One of the major pathways that controls hyphal morphogenesis is the Ras-signaling pathway. We examine the cross-talk between GPI anchor biosynthesis and Ras signaling in We show that the first step of GPI biosynthesis is activated by Ras in This is diametrically opposite to what is reported in Of the two Ras proteins, CaRas1 alone activates GPI-GnT activity; activity is further stimulated by constitutively activated CaRas1. CaRas1 localized to the cytoplasm or endoplasmic reticulum (ER) is sufficient for GPI-GnT activation. Of the six subunits of the GPI--acetylglucosaminyltransferase (GPI-GnT) that catalyze the first step of GPI biosynthesis, CaGpi2 is the key player involved in activating Ras signaling and hyphal morphogenesis. Activation of Ras signaling is independent of the catalytic competence of GPI-GnT. This too is unlike what is observed in where multiple subunits were identified as inhibiting Ras2. Fluorescence resonance energy transfer (FRET) studies indicate a specific physical interaction between CaRas1 and CaGpi2 in the ER, which would explain the ability of CaRas1 to activate GPI-GnT. CaGpi2, in turn, promotes activation of the Ras-signaling pathway and hyphal morphogenesis. The mutant is also more susceptible to macrophage-mediated killing, and macrophage cells show better survival when co-cultured with .

The Role of Secretory Pathways in Candida albicans Pathogenesis

“…Over 115 GPI-anchored proteins have been identified in C. albicans, although only 35% of them have known functions [101]. There has been limited research conducted on the mechanisms of GPI-anchoring in C. albicans, but the process is activated by a Ras-signaling pathway and involves a transamidase enzyme complex [102,103].…”

Generating anchors only to lose them: The unusual story of glycosylphosphatidylinositol anchor biosynthesis and remodeling in yeast and fungi

“…While Cagpi19 and Caeri1 have CWs with higher chitin levels, Cagpi1, Cagpi2, and Cagpi15 have CWs with reduced chitin (unpublished data from the laboratory). While both Cagpi19 and Caeri1 are hyperfilamentous and sensitive to azoles, Cagpi1, Cagpi2 , and Cagpi15 are hypofilamentous and resistant to azoles . A mutually negative regulation is observed between CaGPI2 and CaGPI19 .…”

“…In C. albicans, all GPI‐GnT subunits are essential for activity (44,77 and other unpublished data from the lab). All GPI‐GnT mutants show CW defects and altered hyphal morphogenesis.…”

“…A mutually negative regulation is observed between CaGPI2 and CaGPI19 . CaGpi2 controls hyphal morphogenesis by regulating Ras signaling . Cagpi2 cells are also more susceptible to killing by macrophages and recovery of live MH‐S cells is higher when incubated with Cagpi2 .…”

“…CaGpi2 controls hyphal morphogenesis by regulating Ras signaling . Cagpi2 cells are also more susceptible to killing by macrophages and recovery of live MH‐S cells is higher when incubated with Cagpi2 . CaGPI19 , on the other hand, exhibits a co‐regulation with ERG11, the lanosterol demethylase in the ergosterol biosynthetic pathway and the target of azole antifungals .…”