2. Academic Validation
  3. IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

  • J Exp Med. 2017 Feb;214(2):423-437. doi: 10.1084/jem.20161867.
Michaela A Diamanti 1,  Jalaj Gupta 1,  Moritz Bennecke 2,  Tiago De Oliveira 1,  Mallika Ramakrishnan 1,  Anne K Braczynski 3,  Benjamin Richter 4,  Petra Beli 5,  Yinling Hu 6,  Maya Saleh 7,  Michel Mittelbronn 3,  Ivan Dikic 4,  Florian R Greten 8
Affiliations

Affiliations

  • 1 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
  • 2 Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
  • 3 Edinger Institute (Institute of Neurology), Goethe University Hospital, Goethe University, 60323 Frankfurt, Germany.
  • 4 Institute of Biochemistry II, Buchmann Institute for Molecular Life Sciences, Goethe University School of Medicine, Goethe University, 60323 Frankfurt, Germany.
  • 5 Institute of Molecular Biology, 55128 Mainz, Germany.
  • 6 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
  • 7 Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
  • 8 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany [email protected].
PMID: 28082356 DOI: 10.1084/jem.20161867
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.

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