IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

  • Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.

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Author:Michaela A. Diamanti, Jalaj Gupta, Moritz Bennecke, Tiago de Oliveira, Mallika Ramakrishnan, Anne Kristin Braczynski, Benjamin Richter, Petra BeliORCiDGND, Yinling Hu, Maya Saleh, Michel Guy André MittelbronnORCiDGND, Ivan ĐikićORCiDGND, Florian GretenORCiDGND
URN:urn:nbn:de:hebis:30:3-439578
DOI:https://doi.org/10.1084/jem.20161867
ISSN:1540-9358
ISSN:0022-1007
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28082356
Parent Title (English):Journal of experimental medicine
Publisher:Rockefeller Univ. Press
Place of publication:New York, NY
Document Type:Article
Language:English
Date of Publication (online):2017/08/17
Date of first Publication:2017/01/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/08/17
Volume:214
Issue:2
Page Number:15
First Page:423
Last Page:437
Note:
© 2017 Diamanti et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
HeBIS-PPN:423606247
Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen

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