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

Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nature (Impact Factor: 42.35). 11/2008; 456(7219):264-8. DOI: 10.1038/nature07383
Source: PubMed

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-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta 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.

Download full-text


Available from: Masaaki Komatsu, Jul 08, 2015
  • Source
    • "Given that caspase-1is over-stoichiometric to ASC by just a few fold, the average lengths of individual ASC nucleated caspase-1 filaments in cells may be shorter than those reconstituted in vitro, leading to punctate, rather than filamentous morphology of intact inflammasomes. Once formed, inflammasomes may require active processes such as autophagy for their degradation (Saitoh et al., 2008).This scenario is reminiscent of the case for the filamentous CARMA1/Bcl10/MALT1 signal osome (Qiao et al., 2013), and may represent a general mechanism of disassembly of higher-order signalosomes in innate immunity to terminate signaling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK:
    Cell 03/2014; 156(6):1193-206. DOI:10.1016/j.cell.2014.02.008 · 33.12 Impact Factor
  • Source
    • "Thus, in this model, preventing TRIF cleavage results in increased autophagy following infection that is associated with reduced IL-1b production but decreased numbers of viable intraperitoneal bacteria. This suggests autophagy may well control NLRC4 inflammasome activation following P. aeruginosa infection, as has been found for NLRP3 inflammasome activation (Saitoh et al., 2008); this is considered further in the Discussion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bacterial infection can trigger autophagy and inflammasome activation, but the effects of inflammasome activation on autophagy are unknown. We examined this in the context of Pseudomonas aeruginosa macrophage infection, which triggers NLRC4 inflammasome activation. P. aeruginosa induced autophagy via TLR4 and its adaptor TRIF. NLRC4 and caspase-1 activation following infection attenuated autophagy. Caspase-1 directly cleaved TRIF to diminish TRIF-mediated signaling, resulting in inhibition of autophagy and in reduced type I interferon production. Expression of a caspase-1 resistant TRIF mutant enhanced autophagy and type I interferon production following infection. Preventing TRIF cleavage by caspase-1 in an in vivo model of P. aeruginosa infection resulted in enhanced bacterial autophagy, attenuated IL-1β production, and increased bacterial clearance. Additionally, TRIF cleavage by caspase-1 diminished NLRP3 inflammasome activation. Thus, caspase-1 mediated TRIF cleavage is a key event in controlling autophagy, type I interferon production, and inflammasome activation with important functional consequences.
    Cell host & microbe 02/2014; 15(2):214-27. DOI:10.1016/j.chom.2014.01.010 · 12.19 Impact Factor
  • Source
    • "The ATG5–ATG12 conjugate additionally forms a large protein complex with ATG16L1 which is essential for its function in autophagy but dispensable for its E3-like ligase activity. Depletion of any of ATG3, ATG5–ATG12, ATG16L1 or ATG7 completely abolishes autophagosome formation and leads to neonatal lethality in mouse models highlighting the role of autophagy during neonatal starvation period (Mizushima et al., 2001; Komatsu et al., 2005; Saitoh et al., 2008). "