The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans

Abstract

Summary: Integrating nutrient sensing with the synthesis of complex molecules is a central feature of metabolism. Yet the regulatory mechanisms underlying such integration are often unknown. Here, we establish that the transcription regulators Rtg1/3 are key determinants of sphingolipid homeostasis in the human fungal pathogen Candida albicans. Quantitative analysis of the C. albicans lipidome reveals Rtg1/3-dependent alterations in all complex sphingolipids and their precursors, ceramides. Mutations in the regulators render the fungus susceptible to myriocin, a sphingolipid synthesis inhibitor. Rtg1/3 exert control on the expression of several enzymes involved in the synthesis of sphingolipids’ building blocks, and the regulators are activated upon engulfment of C. albicans cells by human neutrophils. We demonstrate that Rtg1p and Rtg3p are regulated at two levels, one in response to sphingolipids and the other by the nutrient sensor TOR. Our findings, therefore, indicate that the Rtg1/3 system integrates nutrient sensing into the synthesis of complex lipids. : Integrating nutrient sensing with the synthesis of complex molecules, e.g., lipids, is a central feature of cellular metabolism. Moreno-Velásquez et al. establish that the yeast transcription regulators Rtg1 and Rtg3 regulate sphingolipid synthesis and implicate the nutrient sensor kinase TOR in regulating the stability of the Rtg1/3 proteins. Keywords: sphingolipids, Rtg1, Rtg3, yeast, TOR, Candida albicans