IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

Michaela A. Diamanti, Jalaj Gupta, Moritz Bennecke, Tiago De Oliveira, Mallika Ramakrishnan, Anne K. Braczynski, Benjamin Richter, Petra Beli, Yinling Hu, Maya Saleh, Michel Mittelbronn, Ivan Dikic, Florian R. Greten*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)423-437
Number of pages15
JournalJournal of Experimental Medicine
Volume214
Issue number2
DOIs
Publication statusPublished - 2017
Externally publishedYes

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