Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production (original) (raw)
- Letter
- Published: 05 October 2008
- Naonobu Fujita4 na1,
- Myoung Ho Jang2,
- Satoshi Uematsu1,3,
- Bo-Gie Yang1,3,
- Takashi Satoh1,3,
- Hiroko Omori4,
- Takeshi Noda4,
- Naoki Yamamoto5,
- Masaaki Komatsu6,7,8,
- Keiji Tanaka6,
- Taro Kawai1,3,
- Tohru Tsujimura9,
- Osamu Takeuchi1,3,
- Tamotsu Yoshimori4,10 &
- …
- Shizuo Akira1,3
Nature volume 456, pages 264–268 (2008)Cite this article
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Abstract
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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Acknowledgements
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.
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Author notes
- Tatsuya Saitoh and Naonobu Fujita: These authors contributed equally to this work.
Authors and Affiliations
- Laboratory of Host Defense,,
Tatsuya Saitoh, Satoshi Uematsu, Bo-Gie Yang, Takashi Satoh, Taro Kawai, Osamu Takeuchi & Shizuo Akira - Laboratory of Gastrointestinal Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan ,
Myoung Ho Jang - Department of Host Defense,,
Tatsuya Saitoh, Satoshi Uematsu, Bo-Gie Yang, Takashi Satoh, Taro Kawai, Osamu Takeuchi & Shizuo Akira - 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 - AIDS Research Center, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan ,
Naoki Yamamoto - Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan ,
Masaaki Komatsu & Keiji Tanaka - Department of Biochemistry, Juntendo University School of Medicine, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan,
Masaaki Komatsu - PRESTO, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan ,
Masaaki Komatsu - Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan,
Tohru Tsujimura - CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan ,
Tamotsu Yoshimori
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Saitoh, T., Fujita, N., Jang, M. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production.Nature 456, 264–268 (2008). https://doi.org/10.1038/nature07383
- Received: 07 August 2008
- Accepted: 26 August 2008
- Published: 05 October 2008
- Issue Date: 13 November 2008
- DOI: https://doi.org/10.1038/nature07383
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Editorial Summary
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.