The transmembrane segment of a tail-anchored protein determines its degradative fate through dislocation from the endoplasmic reticulum

Jasper H L Claessen; Britta Mueller; Eric Spooner; Valerie L Pivorunas; Hidde L Ploegh

doi:10.1074/jbc.M110.120766

The transmembrane segment of a tail-anchored protein determines its degradative fate through dislocation from the endoplasmic reticulum

J Biol Chem. 2010 Jul 2;285(27):20732-9. doi: 10.1074/jbc.M110.120766. Epub 2010 Apr 30.

Authors

Jasper H L Claessen¹, Britta Mueller, Eric Spooner, Valerie L Pivorunas, Hidde L Ploegh

Affiliation

¹ Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Abstract

Terminally misfolded proteins that accumulate in the endoplasmic reticulum (ER) are dislocated and targeted for ubiquitin-dependent destruction by the proteasome. UBC6e is a tail-anchored E2 ubiquitin-conjugating enzyme that is part of a dislocation complex nucleated by the ER-resident protein SEL1L. Little is known about the turnover of tail-anchored ER proteins. We constructed a set of UBC6e transmembrane domain replacement mutants and found that the tail anchor of UBC6e is vital for its function, its stability, and its mode of membrane integration, the last step dependent on the ASNA1/TRC40 chaperone. We constructed a tail-anchored UBC6e variant that requires for its removal from the ER membrane not only YOD1 and p97, two cytosolic proteins involved in the extraction of ER transmembrane or luminal proteins, but also UBXD8, AUP1 and members of the Derlin family. Degradation of tail-anchored proteins thus relies on components that are also used in other aspects of protein quality control in the ER.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arsenite Transporting ATPases / genetics
Cell Differentiation
Cloning, Molecular
Cystic Fibrosis / genetics
Cystic Fibrosis / metabolism
Cytomegalovirus / genetics
Cytomegalovirus / metabolism
Drug Stability
Endoplasmic Reticulum / enzymology
Endoplasmic Reticulum / metabolism*
Epitopes
Genetic Variation
Hemagglutinins / immunology
Histocompatibility Antigens Class I / immunology
Humans
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / metabolism
Phosphoric Monoester Hydrolases / metabolism
Proteasome Endopeptidase Complex / metabolism*
Protein Folding
Protein Transport
Proteostasis Deficiencies / metabolism
T-Lymphocytes / metabolism
Ubiquitin / metabolism*
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism
Viral Proteins / genetics
Viral Proteins / metabolism

Substances

Epitopes
GET3 protein, human
Hemagglutinins
Histocompatibility Antigens Class I
Ubiquitin
Viral Proteins
Ubiquitin-Conjugating Enzymes
Phosphoric Monoester Hydrolases
Proteasome Endopeptidase Complex
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Arsenite Transporting ATPases