The Sec61 translocon limits IRE1α signaling during the unfolded protein response

ELife
Arunkumar SundaramMalaiyalam Mariappan

Abstract

IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex. In addition, IRE1α oligomerization, activation, and inactivation during ER stress are regulated by Sec61. Loss of the IRE1α-Sec61 translocon interaction as well as severe ER stress conditions causes IRE1α to form higher-order oligomers that exhibit continuous activation and extended cleavage of XBP1u mRNA. Thus, we propose that the Sec61-IRE1α complex defines the extent of IRE1α activity and may determine cell fate decisions during ER stress conditions.

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Citations

Jun 16, 2017·Molecular Biology of the Cell·Nozomu KonoDavid Ron
Jun 1, 2018·Molecular Biology of the Cell·Arunkumar SundaramMalaiyalam Mariappan
Nov 7, 2018·Cold Spring Harbor Perspectives in Biology·Steffen Preissler, David Ron
Jan 28, 2020·The Journal of Cell Biology·Michael J GreyWayne I Lencer
Jun 15, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Daniela RicciYair Argon
Dec 11, 2019·Nature Chemical Biology·Thomas F MartinezAlan Saghatelian
Nov 23, 2017·Frontiers in Physiology·Sven LangRichard Zimmermann
Oct 12, 2018·Nature Reviews. Molecular Cell Biology·Lorenzo GalluzziGuido Kroemer
Nov 15, 2019·F1000Research·G Elif KaragözDiego Acosta-Alvear
Aug 14, 2020·Journal of Cell Science·Hery UrraClaudio Hetz
May 22, 2019·Nature Cell Biology·Roland Malli, Wolfgang F Graier
Feb 6, 2020·Journal of Cell Science·Max Gemmer, Friedrich Förster
Apr 2, 2021·The Journal of Cell Biology·Jacob A Culver, Malaiyalam Mariappan
Dec 17, 2021·Nature Communications·Adrien Le ThomasAvi Ashkenazi

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Methods Mentioned

BETA
protein folding
electrophoresis
ion exchange chromatography
in vitro transcription
glycosylation
confocal microscopy
immunoprecipitation
PCR

Software Mentioned

GraphPad Prism
Leica Application Suite
Image Quant TL

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