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

The EMBO Journal
Oliver SchmidtDavid Teis

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 l...Continue Reading

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Citations

Jan 23, 2020·Nature Communications·Avital Eisenberg-LernerYifat Merbl
Sep 21, 2019·The Journal of Cell Biology·Zhihao Sun, Jeffrey L Brodsky
Jul 23, 2019·The EMBO Journal·Daniel Fonseca, Pedro Carvalho
Dec 10, 2019·FEMS Yeast Research·Ian W Dawes, Gabriel G Perrone
Sep 24, 2020·International Journal of Molecular Sciences·Mafalda Escobar-Henriques, Vincent Anton
Oct 28, 2020·Proceedings of the National Academy of Sciences of the United States of America·Daniel L KoberArun Radhakrishnan
Oct 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Xiao Albert ZhouJiadong Wang
Jan 9, 2021·Trends in Cell Biology·Richa Sardana, Scott D Emr
Jul 10, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Rachel R Kandel, Sonya E Neal
Sep 10, 2021·BioFactors·Jiayin GaoLinxi Chen

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Methods Mentioned

BETA
ubiquitination
SGA
immunoprecipitations
fluorescence microscopy
immunoprecipitation
glycosylation
PCR
genetic modifications
acetylation
electrophoresis

Key Resources (RRID) Mentioned

SCR_014477
SCR_016137
AB_2637089
SCR_014199
SCR_003070

Software Mentioned

ImageJ2
PikoReal
Huygens Professional
MAFFT
Excel
tree
BLAST
Sequest
HMMER
Go SLIM mapper

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