Dynamic changes in complexes of IRE1α, PERK, and ATF6α during endoplasmic reticulum stress

Molecular Biology of the Cell
Arunkumar SundaramMalaiyalam Mariappan

Abstract

The endoplasmic reticulum (ER) localized unfolded protein response (UPR) sensors, IRE1α, PERK, and ATF6α, are activated by the accumulation of misfolded proteins in the ER. It is unclear how the endogenous UPR sensors are regulated by both ER stress and the ER luminal chaperone BiP, which is a negative regulator of UPR sensors. Here we simultaneously examined the changes in the endogenous complexes of UPR sensors by blue native PAGE immunoblotting in unstressed and stressed cells. We found that all three UPR sensors exist as preformed complexes even in unstressed cells. While PERK complexes shift to large complexes, ATF6α complexes are reduced to smaller complexes on ER stress. In contrast, IRE1α complexes were not significantly increased in size on ER stress, unless IRE1α is overexpressed. Surprisingly, depletion of BiP had little impact on the endogenous complexes of UPR sensors. In addition, overexpression of BiP did not significantly affect UPR complexes, but suppressed ER stress mediated activation of IRE1α, ATF6α and, to a lesser extent, PERK. Furthermore, we captured the interaction between IRE1α and misfolded secretory proteins in cells, which suggests that the binding of unfolded proteins to preformed complexes of UPR ...Continue Reading

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Citations

Feb 7, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Congwen WeiHui Zhong
Jun 15, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Daniela RicciYair Argon
Jul 8, 2020·Critical Reviews in Biochemistry and Molecular Biology·Xiaodan QinHui Feng
May 28, 2020·Nature Reviews. Molecular Cell Biology·Claudio HetzRandal J Kaufman
Apr 2, 2019·Frontiers in Molecular Biosciences·Christopher J AdamsMaruf M U Ali
May 25, 2020·Applied Microbiology and Biotechnology·Wei LiShuangquan Liu

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Methods Mentioned

BETA
protein folding
size fractionation
cross-linking assay

Key Resources (RRID) Mentioned

AB_823545
AB_2095847
AB_2241126
AB_398292

Software Mentioned

ImageJ
GraphPad Prism

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