Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production

Inflammatory bowel disease Crohn's disease, a chronic inflammation of the gut, has been linked to over thirty gene loci. Two papers in this issue focus a recent addition to that list, ATG16L1 (Atg16-like 1). Atg16 protein itself was first identified in yeast as an essential gene for the process of autophagy, a system that clears away unwanted cellular components and is involved in the pathogenesis of microbial infection, neurodegeneration and tumorigenesis. Cadwell et al . report a unique role for Atg16L1 in Paneth cells, a type of epithelial cell that secretes granules containing antimicrobial peptides into the intestines. Saitoh et al . show that ATG16L1 plays a role in the inflammatory response in isolated macrophages and in the mouse intestine, as an essential component of the autophagic machinery. This work implicates Atg16L1 in the control of inflammatory immune response and the maintenance of intestinal barrier, both of which are important for the prevention of inflammatory bowel disease. Systems for protein degradation are essential for tight control of the inflammatory immune response 1 , 2 . Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation 3 , 4 , 5 . However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease 6 , 7 , regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8 , 9 ), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1β and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1β. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran