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An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response

Lookup NU author(s): Monika Suwara, Dr Lou Sutcliffe

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). In mammalian cells, UPR signals generated by several ER-membrane-resident proteins, including the bifunctional protein kinase endoribonuclease IRE1 alpha, control cell survival and the decision to execute apoptosis. Processing of XBP1 mRNA by the RNase domain of IRE1a promotes survival of ER stress, whereas activation of the mitogen-activated protein kinase JNK family by IRE1 alpha late in the ER stress response promotes apoptosis. Here, we show that activation of JNK in the ER stress response precedes activation of XBP1. This activation of JNK is dependent on IRE1 alpha and TRAF2 and coincides with JNK-dependent induction of expression of several antiapoptotic genes, including cIap1 (also known as Birc2), cIap2 (also known as Birc3), Xiap and Birc6. ER-stressed Jnk1(-/-) Jnk2(-/-) (Mapk8(-/-) Mapk9(-/-)) mouse embryonic fibroblasts (MEFs) display more pronounced mitochondrial permeability transition and increased caspase 3/7 activity compared to wild-type MEFs. Caspase 3/7 activity is also elevated in ER-stressed cIap1(-/-) cIap2(-/-) and Xiap(-/-) MEFs. These observations suggest that JNK-dependent transcriptional induction of several inhibitors of apoptosis contributes to inhibiting apoptosis early in the ER stress response.


Publication metadata

Author(s): Brown M, Strudwick N, Suwara M, Sutcliffe LK, Mihai AD, Ali AA, Watson JN, Schröder M

Publication type: Article

Publication status: Published

Journal: Journal of Cell Science

Year: 2016

Volume: 129

Issue: 12

Pages: 2317-2328

Print publication date: 15/06/2016

Online publication date: 27/04/2016

Acceptance date: 20/04/2016

Date deposited: 28/10/2016

ISSN (print): 0021-9533

ISSN (electronic): 1477-9137

Publisher: Company of Biologists Ltd.

URL: http://dx.doi.org/10.1242/jcs.179127

DOI: 10.1242/jcs.179127

PubMed id: 27122189


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