title: A time-dependent phase shift in the mammalian unfolded protein response.
abstract: Unfolded or misfolded proteins in the endoplasmic reticulum (ER) must be refolded or degraded to maintain homeostasis of the ER. The ATF6 and IRE1-XBP1 pathways are important for the refolding process in mammalian cells; activation of these transcriptional programs culminates in induction of ER-localized molecular chaperones and folding enzymes. We show here that degradation of misfolded glycoprotein substrates requires transcriptional induction of EDEM (ER degradation-enhancing alpha-mannosidase-like protein), and that this is mediated specifically by IRE1-XBP1 and not by ATF6. As XBP1 is produced after ATF6 activation, our results reveal a time-dependent transition in the mammalian unfolded protein response: an ATF6-mediated unidirectional phase (refolding only) is followed by an XBP1-mediated bidirectional phase (refolding plus degradation) as the response progresses.
authors.affiliation: Graduate School of Biostudies, Kyoto University, Kyoto 606-8304, Japan.
authors.forename: Hiderou
authors.initials: H
authors.lastname: Yoshida
authors.forename: Toshie
authors.initials: T
authors.lastname: Matsui
authors.forename: Nobuko
authors.initials: N
authors.lastname: Hosokawa
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: D051702:Activating Transcription Factor 6; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases; D005786:Gene Expression Regulation / Q000502:physiology*; D005802:Genes, MHC Class II / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008361:Mannosidases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice / Q000196:embryology*; D018345:Mice, Knockout; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000071717:X-Box Binding Protein 1
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D004268:DNA-Binding Proteins; C486654:EDEM1 protein, human; C434526:Edem1 protein, mouse; D006023:Glycoproteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D008156:Luciferases; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D008361:Mannosidases