title: IKKα controls ATG16L1 degradation to prevent ER stress during inflammation.
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/AAmice. 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.
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
authors.forename: Michaela A
authors.identifier: 0000-0003-1971-4225
authors.initials: MA
authors.lastname: Diamanti
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
authors.forename: Jalaj
authors.identifier: 0000-0002-0153-080X
authors.initials: J
authors.lastname: Gupta
authors.affiliation: Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Moritz
authors.identifier: 0000-0002-3896-4345
authors.initials: M
authors.lastname: Bennecke
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
authors.forename: Tiago
authors.identifier: 0000-0002-2502-7897
authors.initials: T
authors.lastname: De Oliveira
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
authors.forename: Mallika
authors.identifier: 0000-0003-3144-2824
authors.initials: M
authors.lastname: Ramakrishnan
authors.affiliation: Edinger Institute (Institute of Neurology), Goethe University Hospital, Goethe University, 60323 Frankfurt, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Braczynski
authors.affiliation: Institute of Biochemistry II, Buchmann Institute for Molecular Life Sciences, Goethe University School of Medicine, Goethe University, 60323 Frankfurt, Germany.
authors.forename: Benjamin
authors.identifier: 0000-0002-4872-8637
authors.initials: B
authors.lastname: Richter
authors.affiliation: Institute of Molecular Biology, 55128 Mainz, Germany.
authors.forename: Petra
authors.identifier: 0000-0001-9507-9820
authors.initials: P
authors.lastname: Beli
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
authors.affiliation: Edinger Institute (Institute of Neurology), Goethe University Hospital, Goethe University, 60323 Frankfurt, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Institute of Biochemistry II, Buchmann Institute for Molecular Life Sciences, Goethe University School of Medicine, Goethe University, 60323 Frankfurt, Germany.
authors.forename: Ivan
authors.identifier: 0000-0001-8156-9511
authors.initials: I
authors.lastname: Dikic
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany greten@gsh.uni-frankfurt.de.
authors.forename: Florian R
authors.identifier: 0000-0002-3928-6080
authors.initials: FR
authors.lastname: Greten
mesh_terms: D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D053454:Caspase 12 / Q000502:physiology; D003092:Colitis / Q000517:prevention & control; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000502:physiology; D051550:I-kappa B Kinase / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D055550:Protein Stability; D056811:Unfolded Protein Response
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D020382:Interleukin-18; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D004722:Endoribonucleases; D053454:Caspase 12