ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING.
Authors
Aden, Konrad
Ito, Go
Sheibani-Tezerji, Raheleh
Kuiper, Jan W
Saveljeva, Svetlana
Häsler, Robert
Bartsch, Kareen
Luzius, Anne
Jentzsch, Marlene
Falk-Paulsen, Maren
Stengel, Stephanie T
Welz, Lina
Schwarzer, Robin
Rabe, Björn
Barchet, Winfried
Hartmann, Gunther
Pasparakis, Manolis
Schreiber, Stefan
Publication Date
2018-11-05Journal Title
J Exp Med
ISSN
0022-1007
Publisher
Rockefeller University Press
Volume
215
Issue
11
Pages
2868-2886
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Aden, K., Tran, F., Ito, G., Sheibani-Tezerji, R., Lipinski, S., Kuiper, J. W., Tschurtschenthaler, M., et al. (2018). ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING.. J Exp Med, 215 (11), 2868-2886. https://doi.org/10.1084/jem.20171029
Abstract
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.
Keywords
Animals, Autophagy-Related Proteins, Caco-2 Cells, Carrier Proteins, Genetic Variation, Humans, Inflammatory Bowel Diseases, Interleukins, Intestinal Mucosa, Membrane Proteins, Mice, Mice, Knockout, Nucleotidyltransferases, Signal Transduction
Sponsorship
European Research Council (260961)
Wellcome Trust (106260/Z/14/Z)
European Research Council (648889)
European Commission Horizon 2020 (H2020) Societal Challenges (733100)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1084/jem.20171029
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279862
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