The GARP Complex is Required for Cellular Sphingolipid Homeostasis

Overview

Journal Elife

Specialty Biology

Date 2015 Sep 11

PMID 26357016

Citations 56

Authors

Florian Frohlich

Constance Petit

Nora Kory

Romain Christiano

Hans-Kristian Hannibal-Bach

Morven Graham

Xinran Liu

Christer S Ejsing

Robert V Farese

Tobias C Walther

Affiliations

Soon will be listed here.

Abstract

Sphingolipids are abundant membrane components and important signaling molecules in eukaryotic cells. Their levels and localization are tightly regulated. However, the mechanisms underlying this regulation remain largely unknown. In this study, we identify the Golgi-associated retrograde protein (GARP) complex, which functions in endosome-to-Golgi retrograde vesicular transport, as a critical player in sphingolipid homeostasis. GARP deficiency leads to accumulation of sphingolipid synthesis intermediates, changes in sterol distribution, and lysosomal dysfunction. A GARP complex mutation analogous to a VPS53 allele causing progressive cerebello-cerebral atrophy type 2 (PCCA2) in humans exhibits similar, albeit weaker, phenotypes in yeast, providing mechanistic insights into disease pathogenesis. Inhibition of the first step of de novo sphingolipid synthesis is sufficient to mitigate many of the phenotypes of GARP-deficient yeast or mammalian cells. Together, these data show that GARP is essential for cellular sphingolipid homeostasis and suggest a therapeutic strategy for the treatment of PCCA2.

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