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PMID: 28082356 Published · ppublish English Journal Article

IKKα controls ATG16L1 degradation to prevent ER stress during inflammation.

The Journal of experimental medicine ·Vol. 214 ·No. 2 ·2017-00-00 ·Pages 423-437

Diamanti MA, Gupta J, Bennecke M, De Oliveira T, Ramakrishnan M, Braczynski AK, Richter B, Beli P, Hu Y, Saleh M, Mittelbronn M, Dikic I, Greten FR

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.

MeSH Terms
Animals Autophagy-Related Proteins Carrier Proteins/chemistry,metabolism Caspase 12/physiology Colitis/prevention & control Endoplasmic Reticulum Stress Endoribonucleases/physiology I-kappa B Kinase/physiology Inflammation/metabolism Interleukin-18/metabolism Mice NF-kappa B/physiology Nod2 Signaling Adaptor Protein/physiology Protein Serine-Threonine Kinases/physiology Protein Stability Unfolded Protein Response
Chemicals
Atg16l1 protein, mouse Autophagy-Related Proteins Carrier Proteins Interleukin-18 NF-kappa B Nod2 Signaling Adaptor Protein Nod2 protein, mouse Ern1 protein, mouse Protein Serine-Threonine Kinases I-kappa B Kinase Endoribonucleases Caspase 12
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Diamanti Michaela A ORCID
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
Gupta Jalaj ORCID
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
Bennecke Moritz ORCID
Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
De Oliveira Tiago ORCID
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
Ramakrishnan Mallika ORCID
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
Braczynski Anne K
Edinger Institute (Institute of Neurology), Goethe University Hospital, Goethe University, 60323 Frankfurt, Germany.
Richter Benjamin ORCID
Institute of Biochemistry II, Buchmann Institute for Molecular Life Sciences, Goethe University School of Medicine, Goethe University, 60323 Frankfurt, Germany.
Beli Petra ORCID
Institute of Molecular Biology, 55128 Mainz, Germany.
Hu Yinling
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
Saleh Maya
Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Mittelbronn Michel
Edinger Institute (Institute of Neurology), Goethe University Hospital, Goethe University, 60323 Frankfurt, Germany.
Dikic Ivan ORCID
Institute of Biochemistry II, Buchmann Institute for Molecular Life Sciences, Goethe University School of Medicine, Goethe University, 60323 Frankfurt, Germany.
Greten Florian R ORCID
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany greten@gsh.uni-frankfurt.de.
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20161867
Email
greten@gsh.uni-frankfurt.de
Published
2017-00-00
Epub
2017-00-12
Pages
423-437
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC5294863
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20161867 PMC Full Text View journal details
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