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

Sergio D Moreno-Velásquez,Su Hlaing Tint,Valentina Del Olmo Toledo,Sanda Torsin,Sonakshi De,J Christian Pérez

doi:10.1016/j.celrep.2019.12.022

Sergio D Moreno-Velásquez, Su Hlaing Tint + Show 4 more

Open Access

https://doi.org/10.1016/j.celrep.2019.12.022

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Abstract

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.

Highlights

Integrating nutrient sensing with the synthesis of complex molecules, e.g., lipids, is a central feature of cellular metabolism
This multimeric protein complex responds to nitrogen, carbon, and phosphate availability and impinges upon essential processes, including cell growth, protein biosynthesis, organization of the actin cytoskeleton, and endocytosis (Liu et al, 2017; Loewith and Hall, 2011). mechanistic target of rapamycin (mTOR) downstream effectors have primarily been studied in mammals and model organisms; less is known about the signaling and metabolic pathways linked to TOR in other medically relevant microbes
Metabolome Analysis in C. albicans Links the Rtg1/3 System to Lipid Biosynthesis The biology of the heterodimeric transcription regulator encoded by the genes RTG1 and RTG3 has primarily been investigated in S. cerevisiae

Summary

Introduction

Integrating nutrient sensing with the synthesis of complex molecules, e.g., lipids, is a central feature of cellular metabolism. A major, evolutionarily conserved nutrient sensing network is the mechanistic target of rapamycin (mTOR) pathway (Sabatini, 2017) This multimeric protein complex responds to nitrogen, carbon, and phosphate availability and impinges upon essential processes, including cell growth, protein biosynthesis, organization of the actin cytoskeleton, and endocytosis (Liu et al, 2017; Loewith and Hall, 2011). They are ubiquitous components of membranes and can act as signaling molecules (Hannun and Obeid, 2018) Key cellular processes such as cell growth, endocytosis, nutrient acquisition, and protein trafficking depend, at least in part, on sphingolipids (Dickson, 2010; Teixeira and Costa, 2016). The mechanisms that maintain sphingolipid homeostasis in these organisms, remain largely unexplored

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