Systems for protein degradation are essential for tight control of the inflammatory immune response1,2. 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 inflammation3,4,5. 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 disease6,7, 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 sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1β and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.
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We are grateful to T. Kitamura, S. Yamaoka and N. Mizushima for providing materials. We thank K. J. Ishii, M. Yamamoto and members of the Laboratory of Host Defense for discussions; Y. Fujiwara, M. Shiokawa, R. Nakayama and N. Kitagaki for technical assistance; and M. Hashimoto and E. Kamada for secretarial assistance. This work was in part supported by grants from NIH (AI070167) and the Ministry of Health, Labour and Welfare of Japan, and by Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Author Contributions T.S. generated the Atg16L1-deficient mice and performed the immunological experiments. N.F. performed the cell biology experiments. N.Y. generated the retroviral vector. M.K. and K.T. generated the Atg7-deficient mice. T.T. performed histological analysis of mice. M.H.J., S.U., B.-G.Y., T.S., H.O., T.N., T.K. and O.T. helped with experiments. T.Y. designed the cell biology research. S.A. supervised the overall research project.
This file contains Supplementary Figures 1-22 with Legends.