Endosome and Golgi-associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism.
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
Sphingolipids
/ metabolism
Valosin Containing Protein
/ metabolism
Golgi
endosomes
proteasome
sphingolipids
ubiquitin
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
22
12
2018
revised:
08
05
2019
accepted:
08
05
2019
entrez:
2
8
2019
pubmed:
2
8
2019
medline:
24
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31368600
doi: 10.15252/embj.2018101433
pmc: PMC6669922
doi:
Substances chimiques
Membrane Proteins
0
Orm2 protein, S cerevisiae
0
Saccharomyces cerevisiae Proteins
0
Sphingolipids
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
CDC48 protein, S cerevisiae
EC 3.6.4.-
Valosin Containing Protein
EC 3.6.4.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e101433Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : FR 3647/2-1
Pays : International
Organisme : Austrian Science Fund
ID : W1101-B18
Pays : International
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : SFB 944
Pays : International
Organisme : Austrian Science Fund
ID : P30263
Pays : International
Organisme : European Molecular Biology Organization (EMBO)
ID : ALTF 642-2012
Pays : International
Organisme : European Molecular Biology Organization (EMBO)
ID : GA-2010-267146
Pays : International
Organisme : Austrian Science Fund FWF
ID : P 29583
Pays : Austria
Organisme : ETH Zürich
Pays : International
Organisme : MUI-START
ID : 2013042023
Pays : International
Organisme : Austrian Science Fund
ID : FWF-Y444-B12
Pays : International
Organisme : EC|FP7|FP7 Ideas: European Research Council (FP7 Ideas)
Pays : International
Organisme : Swiss National Science Foundation
Pays : Switzerland
Organisme : Austrian Science Fund
ID : P29583
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
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