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

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

Abstract

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.

Keywords: Golgi; endosomes; proteasome; sphingolipids; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum-Associated Degradation
  • Golgi Apparatus / metabolism
  • Lipid Metabolism
  • Membrane Proteins / metabolism
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sphingolipids / metabolism*
  • Valosin Containing Protein / metabolism*

Substances

  • Membrane Proteins
  • Orm2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sphingolipids
  • Proteasome Endopeptidase Complex
  • CDC48 protein, S cerevisiae
  • Valosin Containing Protein