A time-dependent phase shift in the mammalian unfolded protein response.
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.
Yoshida
Hiderou
H
Graduate School of Biostudies, Kyoto University, Kyoto 606-8304, Japan.
Matsui
Toshie
T
Hosokawa
Nobuko
N
Kaufman
Randal J
RJ
Nagata
Kazuhiro
K
Mori
Kazutoshi
K
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
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