Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane.
Polypeptides that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated from the ER membrane to the cytosol where they are degraded by the proteasome. Derlin-1, a member of a family of proteins that bears homology to yeast Der1p, was identified as a factor that is required for the human cytomegalovirus US11-mediated dislocation of class I MHC heavy chains from the ER membrane to the cytosol. Derlin-1 acts in concert with the AAA ATPase p97 to remove dislocation substrate proteins from the ER membrane, but it is unknown whether other factors aid Derlin-1 in its function. Mammalian genomes encode two additional, related proteins (Derlin-2 and Derlin-3). The similarity of the mammalian Derlin-2 and Derlin-3 proteins to yeast Der1p suggested that these as-yet-uncharacterized Derlins also may play a role in ER protein degradation. We demonstrate here that Derlin-2 is an ER-resident protein that, similar to Derlin-1, participates in the degradation of proteins from the ER. Furthermore, we show that Derlin-2 forms a robust multiprotein complex with the p97 AAA ATPase as well as the mammalian orthologs of the yeast Hrd1p/Hrd3p ubiquitin-ligase complex. The data presented here define a set of interactions between proteins involved in dislocation of misfolded polypeptides from the ER.
Lilley
Brendan N
BN
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Ploegh
Hidde L
HL
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*
C487709:DERL1 protein, human; C513305:DERL2 protein, human; C513304:Derl2 protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D000251:Adenosine Triphosphatases; C404942:p97 ATPase