title: The transmembrane segment of a tail-anchored protein determines its degradative fate through dislocation from the endoplasmic reticulum.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Jasper H L
authors.initials: JH
authors.lastname: Claessen
authors.forename: Britta
authors.initials: B
authors.lastname: Mueller
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Pivorunas
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
mesh_terms: D000818:Animals; D053501:Arsenite Transporting ATPases / Q000235:genetics; D002454:Cell Differentiation; D003001:Cloning, Molecular; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism; D004355:Drug Stability; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D000939:Epitopes; D014644:Genetic Variation; D006388:Hemagglutinins / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D021381:Protein Transport; D057165:Proteostasis Deficiencies / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000939:Epitopes; C489667:GET3 protein, human; D006388:Hemagglutinins; D015395:Histocompatibility Antigens Class I; D025801:Ubiquitin; D014764:Viral Proteins; D044763:Ubiquitin-Conjugating Enzymes; D010744:Phosphoric Monoester Hydrolases; D046988:Proteasome Endopeptidase Complex; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; D053501:Arsenite Transporting ATPases