title: Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane.
abstract: Misfolded proteins are eliminated from the endoplasmic reticulum (ER) by retrotranslocation into the cytosol, a pathway hijacked by certain viruses to destroy MHC class I heavy chains. The translocation of polypeptides across the ER membrane requires their polyubiquitination and subsequent extraction from the membrane by the p97 ATPase [also called valosin-containing protein (VCP) or, in yeast, Cdc48]. In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). How the ubiquitination machinery is recruited to the p97/Derlin/VIMP complex is unclear. Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1. During retrotranslocation, a substrate first interacts with Derlin-1 before p97 and other factors join the complex. These data, together with the fact that Derlin-1 is a multispanning membrane protein forming homo-oligomers, support the idea that Derlin-1 is part of a retrotranslocation channel that is associated with both the polyubiquitination and p97-ATPase machineries.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shibata
authors.forename: Marjolein
authors.initials: M
authors.lastname: Kikkert
authors.forename: Sjaak
authors.initials: S
authors.lastname: van Voorden
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Wiertz
authors.forename: Tom A
authors.initials: TA
authors.lastname: Rapoport
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology; D051140:Selenoproteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C487709:DERL1 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010446:Peptide Fragments; C487710:SELENOS protein, human; D051140:Selenoproteins; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C404942:p97 ATPase