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IKK alpha controls ATG16L1 degradation to prevent ER stress during inflammation

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

  2. Author Address

    Inst Tumor Biol & Expt Therapy, Georg Speyer Haus, D-60596 Frankfurt, Germany.Tech Univ Munich, Klinikum Rechts Isar, Inst Mol Immunol, D-81675 Munich, Germany.Goethe Univ, Goethe Univ Hosp, Inst Neurol, Edinger Inst, D-60323 Frankfurt, Germany.Goethe Univ, Sch Med, Buchmann Inst Mol Life Sci, Inst Biochem 2, D-60323 Frankfurt, Germany.Inst Mol Biol, D-55128 Mainz, Germany.NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA.McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.
    1. Year: 2017
    2. Date: 2017-02-01
  2. Journal: JOURNAL OF EXPERIMENTAL MEDICINE
  3. ROCKEFELLER UNIV PRESS,
    1. 214
    2. 2
    3. Pages: 423-437
  5. Type of Article: Article
  6. ISSN: 0022-1007
  1. Abstract:

    Inhibition of the I kappa B 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 IKK alpha kinase (Ikk alpha(AA/AA)), we show that loss of IKK alpha function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKK alpha-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 Ikk alpha(AA/AA) mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKK alpha-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKK alpha 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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External Sources

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  2. DOI: 10.1084/jem.20161867
  3. View record in Web of Science®
  4. WOS: 000394251400011

Library Notes

  1. Fiscal Year: FY2016-2017
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