Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation.
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.
Oda
Yukako
Y
Department of Molecular and Cellular Biology Institute for Frontier Medical Sciences, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Okada
Tetsuya
T
Yoshida
Hiderou
H
Kaufman
Randal J
RJ
Nagata
Kazuhiro
K
Mori
Kazutoshi
K
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
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