Letter | Published:

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

Nature volume 456, pages 264268 (13 November 2008) | Download Citation



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.

Author information

Author notes

    • Tatsuya Saitoh
    •  & Naonobu Fujita

    These authors contributed equally to this work.


  1. Laboratory of Host Defense,

    • Tatsuya Saitoh
    • , Satoshi Uematsu
    • , Bo-Gie Yang
    • , Takashi Satoh
    • , Taro Kawai
    • , Osamu Takeuchi
    •  & Shizuo Akira
  2. Laboratory of Gastrointestinal Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

    • Myoung Ho Jang
  3. Department of Host Defense,

    • Tatsuya Saitoh
    • , Satoshi Uematsu
    • , Bo-Gie Yang
    • , Takashi Satoh
    • , Taro Kawai
    • , Osamu Takeuchi
    •  & Shizuo Akira
  4. Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

    • Naonobu Fujita
    • , Hiroko Omori
    • , Takeshi Noda
    •  & Tamotsu Yoshimori
  5. AIDS Research Center, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan

    • Naoki Yamamoto
  6. Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan

    • Masaaki Komatsu
    •  & Keiji Tanaka
  7. Department of Biochemistry, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan

    • Masaaki Komatsu
  8. PRESTO, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan

    • Masaaki Komatsu
  9. Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan

    • Tohru Tsujimura
  10. CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan

    • Tamotsu Yoshimori


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Corresponding author

Correspondence to Shizuo Akira.

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