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ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING.

Konrad Aden | Florian Tran | Go Ito | Raheleh Sheibani-Tezerji | Simone Lipinski | Jan W Kuiper | Markus Tschurtschenthaler | Svetlana Saveljeva | Joya Bhattacharyya | Robert Häsler | Kareen Bartsch | Anne Luzius | Marlene Jentzsch | Maren Falk-Paulsen | Stephanie T Stengel | Lina Welz | Robin Schwarzer | Björn Rabe | Winfried Barchet | Stefan Krautwald | Gunther Hartmann | Manolis Pasparakis | Richard S Blumberg | Stefan Schreiber | Arthur Kaser | Philip Rosenstiel
The Journal of experimental medicine | 2018

A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1 ΔIEC intestinal organoids. IFN-I signals amplify epithelial TNF production downstream of IL-22 and contribute to necroptotic cell death. In vivo, IL-22 treatment in Atg16l1 ΔIEC and Atg16l1 ΔIEC/Xbp1 ΔIEC mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death. Therapeutic blockade of IFN-I signaling ameliorates IL-22-induced ileal inflammation in Atg16l1 ΔIEC mice. Our data demonstrate an unexpected role of ATG16L1 in coordinating the outcome of IL-22 signaling in the intestinal epithelium.

Pubmed ID: 30254094

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: R37 DK044319
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK088199
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK051362
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK053056
  • Agency: Wellcome Trust, United Kingdom
    Id: 106260/Z/14/Z
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK034854
  • Agency: Wellcome Trust, United Kingdom
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK044319
  • Agency: NIDDK NIH HHS, United States
    Id: R56 DK053056

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