A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.
Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation is an important physiological adaptation to ER stress. This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. Here we identify a p97-interacting membrane protein complex in the mammalian ER that links these two events. The central component of the complex, Derlin-1, is a homologue of Der1, a yeast protein whose inactivation prevents the elimination of misfolded luminal ER proteins. Derlin-1 associates with different substrates as they move through the membrane, and inactivation of Derlin-1 in C. elegans causes ER stress. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor.
Ye
Yihong
Y
Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Shibata
Yoko
Y
Yun
Chi
C
Ron
David
D
Rapoport
Tom A
TA
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism; D051140:Selenoproteins; D014764:Viral Proteins / Q000378:metabolism
C487709:DERL1 protein, human; D015395:Histocompatibility Antigens Class I; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C487710:SELENOS protein, human; D051140:Selenoproteins; C074546:US11 protein, herpesvirus; D014764:Viral Proteins; D000251:Adenosine Triphosphatases; C404942:p97 ATPase