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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , & Immunity by ubiquitylation: A reversible process of modification. Nature Rev. Immunol. 5, 941–952 (2005)

  2. 2.

    et al. Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Blood 110, 962–971 (2007)

  3. 3.

    Molecular dissection of autophagy: Two ubiquitin-like systems. Nature Rev. Mol. Cell Biol. 2, 211–216 (2001)

  4. 4.

    , , & Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008)

  5. 5.

    & Unveiling the roles of autophagy in innate and adaptive immunity. Nature Rev. Immunol. 7, 767–777 (2007)

  6. 6.

    et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007)

  7. 7.

    et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007)

  8. 8.

    , & Pathogen recognition and innate immunity. Cell 124, 783–801 (2006)

  9. 9.

    et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003)

  10. 10.

    et al. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J. Cell Sci. 116, 1679–1688 (2003)

  11. 11.

    , , , & The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol. Biol. Cell 19, 2092–2100 (2008)

  12. 12.

    et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004)

  13. 13.

    et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005)

  14. 14.

    , , , & Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315, 1398–1401 (2007)

  15. 15.

    et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253–1257 (2007)

  16. 16.

    , & Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007)

  17. 17.

    , , & The inflammasome: A danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007)

  18. 18.

    et al. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428, 341–345 (2004)

  19. 19.

    et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918–931 (2007)

  20. 20.

    et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008)

  21. 21.

    , , , & A key role for redox signaling in rapid P2X7 receptor-induced IL-1beta processing in human monocytes. J. Immunol. 180, 8410–8420 (2008)

  22. 22.

    et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135–144 (2007)

  23. 23.

    , , , & Toll-like receptors control autophagy. EMBO J. 27, 1110–1121 (2008)

  24. 24.

    et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006)

  25. 25.

    et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007)

  26. 26.

    et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005)

  27. 27.

    et al. Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1β processing. Science 307, 737–738 (2005)

  28. 28.

    et al. Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice. J. Gastroenterol. Hepatol. 18, 960–969 (2003)

  29. 29.

    , & Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006)

  30. 30.

    et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004)

  31. 31.

    et al. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol. Biol. Cell advance online publication, doi: 10.1091/mbc.E08-03-0312 (3 September 2008)

Download references


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


  1. Search for Tatsuya Saitoh in:

  2. Search for Naonobu Fujita in:

  3. Search for Myoung Ho Jang in:

  4. Search for Satoshi Uematsu in:

  5. Search for Bo-Gie Yang in:

  6. Search for Takashi Satoh in:

  7. Search for Hiroko Omori in:

  8. Search for Takeshi Noda in:

  9. Search for Naoki Yamamoto in:

  10. Search for Masaaki Komatsu in:

  11. Search for Keiji Tanaka in:

  12. Search for Taro Kawai in:

  13. Search for Tohru Tsujimura in:

  14. Search for Osamu Takeuchi in:

  15. Search for Tamotsu Yoshimori in:

  16. Search for Shizuo Akira in:

Corresponding author

Correspondence to Shizuo Akira.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-22 with Legends.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.