The GARP complex is required for filamentation in Candida albicans

Abstract

Abstract Candida albicans is an opportunistic fungal pathogen that causes superficial infections in immunocompetent individuals, as well as life-threatening systemic disease in immunocompromised patients. A key virulence trait of this pathogen is its ability to transition between yeast and filamentous morphologies. A functional genomic screen to identify novel regulators of filamentation previously revealed VPS53 as being important for morphogenesis. Vps53 belongs to the Golgi-associated retrograde protein (GARP) complex, which mediates retrograde trafficking from the endosome to the trans-Golgi network. Here, we explored the role of the entire GARP complex in regulating morphogenesis. Deletion of any of the four genes encoding GARP complex subunits severely impaired filamentation in response to diverse filament-inducing cues, including upon internalization by macrophages. Genetic pathway analysis revealed that while hyperactivation of protein kinase A (PKA) signaling is insufficient to drive filamentation in GARP complex mutants, these strains are capable of filamentation upon overexpression of transcriptional activators or upon deletion of transcriptional repressors of hyphal morphogenesis. Finally, compromise of the GARP complex induced lipotoxicity, and pharmacological inhibition of sphingolipid biosynthesis phenocopied genetic compromise of the GARP complex by impairing filamentation. Together, this work identifies the GARP complex as an important mediator of filamentation in response to multiple inducing cues, maps genetic circuitry important for filamentation upon compromise of GARP function, and supports a model whereby GARP deficiency impairs lipid homeostasis, which is important for supporting filamentous growth in C. albicans.