A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress.
Endoplasmic Reticulum
/ metabolism
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress
Endoribonucleases
/ metabolism
Gene Expression Regulation
Gene Knockout Techniques
HEK293 Cells
Heat-Shock Proteins
/ metabolism
Humans
Membrane Transport Proteins
/ genetics
Models, Biological
Molecular Chaperones
/ genetics
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Protein Serine-Threonine Kinases
/ metabolism
RNA Splicing
RNA-Binding Proteins
/ genetics
SEC Translocation Channels
/ genetics
Signal Transduction
Transcription Factors
/ genetics
Unfolded Protein Response
X-Box Binding Protein 1
/ genetics
ER stress
IRE1
Sec61 translocon
endoplasmic reticulum
protein translocation
unfolded protein response
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 12 2020
29 12 2020
Historique:
received:
15
04
2020
revised:
14
09
2020
accepted:
06
12
2020
entrez:
30
12
2020
pubmed:
31
12
2020
medline:
14
10
2021
Statut:
ppublish
Résumé
Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1α endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress, thereby attenuating IRE1α. Although sustained activation of IRE1α is linked to human diseases, it is not clear how IRE1α is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1α/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1α. This leads to inhibition of higher-order oligomerization and attenuation of IRE1α RNase activity during prolonged ER stress. In Sec63-deficient cells, IRE1α remains activated for a long period of time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to regulate the dynamics of IRE1α signaling in cells.
Identifiants
pubmed: 33378667
pii: S2211-1247(20)31552-7
doi: 10.1016/j.celrep.2020.108563
pmc: PMC7809255
mid: NIHMS1658638
pii:
doi:
Substances chimiques
Endoplasmic Reticulum Chaperone BiP
0
Heat-Shock Proteins
0
Membrane Transport Proteins
0
Molecular Chaperones
0
RNA-Binding Proteins
0
SEC Translocation Channels
0
SEC62 protein, human
0
SEC63 protein, human
0
Transcription Factors
0
X-Box Binding Protein 1
0
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
108563Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM117386
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG056800
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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