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EMBO J. 2019 Aug 1;38(15):e101433. doi: 10.15252/embj.2018101433. Epub 2019 May 27.

Endosome and Golgi-associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism.

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Division of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Department of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany.
INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Centre de Recherche des Cordeliers, Université Paris Diderot, Paris, France.
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria.
Division of Clinical Biochemistry, Protein Micro-Analysis Facility, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Biochemistry, ETH-Zürich, Zurich, Switzerland.


Cellular homeostasis requires the ubiquitin-dependent degradation of membrane proteins. This was assumed to be mediated exclusively either by endoplasmic reticulum-associated degradation (ERAD) or by endosomal sorting complexes required for transport (ESCRT)-dependent lysosomal degradation. We identified in Saccharomyces cerevisiae an additional pathway that selectively extracts membrane proteins at Golgi and endosomes for degradation by cytosolic proteasomes. One endogenous substrate of this endosome and Golgi-associated degradation pathway (EGAD) is the ER-resident membrane protein Orm2, a negative regulator of sphingolipid biosynthesis. Orm2 degradation is initiated by phosphorylation, which triggers its ER export. Once on Golgi and endosomes, Orm2 is poly-ubiquitinated by the membrane-embedded "Defective in SREBP cleavage" (Dsc) ubiquitin ligase complex. Cdc48/VCP then extracts ubiquitinated Orm2 from membranes, which is tightly coupled to the proteasomal degradation of Orm2. Thereby, EGAD prevents the accumulation of Orm2 at the ER and in post-ER compartments and promotes the controlled de-repression of sphingolipid biosynthesis. Thus, the selective degradation of membrane proteins by EGAD contributes to proteostasis and lipid homeostasis in eukaryotic cells.


Golgi; endosomes; proteasome; sphingolipids; ubiquitin

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