IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

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.