Repository logo

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

Change log


Aden, Konrad 
Ito, Go 
Sheibani-Tezerji, Raheleh 


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.



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, Interleukin-22

Journal Title

J Exp Med

Conference Name

Journal ISSN


Volume Title



Rockefeller University Press
European Research Council (260961)
Wellcome Trust (106260/Z/14/Z)
European Research Council (648889)
European Commission Horizon 2020 (H2020) Societal Challenges (733100)