The GARP complex is required for cellular sphingolipid homeostasis
- Harvard T.H. Chan School of Public Health, United States
- University of Southern Denmark, Denmark
- Yale School of Medicine, United States
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. Here, 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.
Article and author information
Author details
Reviewing Editor
- Peter Tontonoz, Howard Hughes Medical Institute, University of California, Los Angeles, United States
Version history
- Received: May 14, 2015
- Accepted: September 9, 2015
- Accepted Manuscript published: September 10, 2015 (version 1)
- Version of Record published: October 12, 2015 (version 2)
Copyright
© 2015, Fröhlich et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The GARP complex is required for cellular sphingolipid homeostasis
eLife 4:e08712.
https://doi.org/10.7554/eLife.08712
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