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

Tatsuya Saitoh, Naonobu Fujita, Myoung Ho Jang, Satoshi Uematsu, Bo Gie Yang, Takashi Satoh, Hiroko Omori, Takeshi Noda, Naoki Yamamoto, Masaaki Komatsu, Keiji Tanaka, Taro Kawai, Tohru Tsujimura, Osamu Takeuchi, Tamotsu Yoshimori, Shizuo Akira

    Research output: Contribution to journalArticlepeer-review

    1412 Citations (Scopus)

    Abstract

    Systems for protein degradation are essential for tight control of the inflammatory immune response. 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. 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, 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.

    Original languageEnglish
    Pages (from-to)264-268
    Number of pages5
    JournalNature
    Volume456
    Issue number7219
    DOIs
    Publication statusPublished - 2008 Nov 13

    ASJC Scopus subject areas

    • General

    Fingerprint Dive into the research topics of 'Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production'. Together they form a unique fingerprint.

    Cite this