title: Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation.
abstract: Proteins that are unfolded or misfolded in the endoplasmic reticulum (ER) must be refolded or degraded to maintain the homeostasis of the ER. Components of both productive folding and ER-associated degradation (ERAD) mechanisms are known to be up-regulated by the unfolded protein response (UPR). We describe two novel components of mammalian ERAD, Derlin-2 and -3, which show weak homology to Der1p, a transmembrane protein involved in yeast ERAD. Both Derlin-2 and -3 are up-regulated by the UPR, and at least Derlin-2 is a target of the IRE1 branch of the response, which is known to up-regulate ER degradation enhancing alpha-mannosidase-like protein (EDEM) and EDEM2, receptor-like molecules for misfolded glycoprotein. Overexpression of Derlin-2 or -3 accelerated degradation of misfolded glycoprotein, whereas their knockdown blocked degradation. Derlin-2 and -3 are associated with EDEM and p97, a cytosolic ATPase responsible for extraction of ERAD substrates. These findings indicate that Derlin-2 and -3 provide the missing link between EDEM and p97 in the process of degrading misfolded glycoproteins.
authors.affiliation: Department of Molecular and Cellular Biology Institute for Frontier Medical Sciences, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Oda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okada
authors.forename: Hiderou
authors.initials: H
authors.lastname: Yoshida
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006023:Glycoproteins; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D006656:Protamine Kinase / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism; D043323:alpha-Mannosidase
chemical_list: C098515:DER1 protein, S cerevisiae; C487709:DERL1 protein, human; C513305:DERL2 protein, human; C509686:DERL3 protein, human; D004268:DNA-Binding Proteins; C513304:Derl2 protein, mouse; C486654:EDEM1 protein, human; C434526:Edem1 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; D006360:Heat-Shock Proteins; D037102:Lectins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000515:alpha 1-Antitrypsin; D014415:Tunicamycin; C486556:Ern2 protein, mouse; D006656:Protamine Kinase; D017346:Protein Serine-Threonine Kinases; C587020:Edem2 protein, mouse; D043323:alpha-Mannosidase; D000251:Adenosine Triphosphatases; C404942:p97 ATPase