Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1 beta production. Nature 456: 264-268

Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nature (Impact Factor: 41.46). 11/2008; 456(7219):264-8. DOI: 10.1038/nature07383
Source: PubMed


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.

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    • "Autophagy is also required for the degradation of p62/SQSTM1, an activator of NF-kB (Sanz et al., 1999; Duran et al., 2008; Ling et al., 2012). Through these mechanisms, autophagy dampens the transcription and/or maturation of pro-inflammatory cytokines to suppress inflammation (Saitoh et al., 2008; Lee et al., 2011). "
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    ABSTRACT: HBV and one of its encoded proteins, HBV X protein (HBx), have been shown to induce autophagy in hepatoma cells. Substantial evidence indicates that autophagy is a potent suppressor of inflammation. However, sporadic reports suggest that autophagy could promote pro-inflammatory cytokine expression and inflammation in some biological contexts. Here we show that overexpression of HBx induces LC3B-positive autophagosome formation, increases autophagic flux and enhances the expression of ATG5, ATG7, and LC3B-II in normal hepatocytes. Abrogation of autophagy by small interfering RNA against ATG5 and ATG7 prevents HBx-induced formation of autophagosomes. Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-κB and production of interleukin-6 (IL-6), IL-8 and CXCL2. These findings suggest that autophagy is required for HBx-induced nuclear factor-κB activation and pro-inflammatory cytokine production and could shed new light on the complex role of autophagy in the modulation of inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 02/2015; 230(10). DOI:10.1002/jcp.24967 · 3.84 Impact Factor
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    • "Several studies have reported that autophagy and/or autophagy-related proteins play an important role in regulating mitochondria integrity, ROS generation, and the subsequent NLRP3 activation. Macrophages treated with 3-methyladenine (3MA), a chemical inhibitor of autophagy, or macrophages with the deletion of several autophagic components, including ATG16L1, ATG7, Beclin 1, and LC3, impair mitochondrial homeostasis and further induce more caspase-1 activation and IL-1β secretion in response to solely LPS or LPS+NLRP3 agonists [29, 47]. These data strongly suggest that autophagy negatively regulates the NLRP3 inflammasome activity. "
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    ABSTRACT: Aging, a natural physiological process, is characterized by a progressive loss of physiological integrity. Loss of cellular homeostasis in the aging process results from different sources, including changes in genes, cell imbalance, and dysregulation of the host-defense systems. Innate immunity dysfunctions during aging are connected with several human pathologies, including metabolic disorders and cardiovascular diseases. Recent studies have clearly indicated that the decline in autophagic capacity that accompanies aging results in the accumulation of dysfunctional mitochondria, reactive oxygen species (ROS) production, and further process dysfunction of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation in the macrophages, which produce the proinflammatory cytokines. These factors impair cellular housekeeping and expose cells to higher risk in many age-related diseases, such as atherosclerosis and type 2 diabetes. In this review, we investigated the relationship between dysregulation of the inflammasome activation and perturbed autophagy with aging as well as the possible molecular mechanisms. We also summarized the natural compounds from food intake, which have potential to reduce the inflammasome activation and enhance autophagy and can further improve the age-related diseases discussed in this paper.
    BioMed Research International 09/2014; 2014:297293. DOI:10.1155/2014/297293 · 2.71 Impact Factor
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    • "This regulation has been most extensively studied for IL-1β. It was observed that IL-1β production is enhanced upon macroautophagy deficiency, leading to gut inflammation in mice with reduced macroautophagy levels (Atg16L1 hypomorphic mice) (Saitoh et al., 2008; Cadwell et al., 2010; Nakahira et al., 2011; Zhou et al., 2011; Lupfer et al., 2013; van den Burgh et al., 2014). Accordingly, Atg16L1 mutations that compromise macroautophagy have been identified in Crohn's disease patients with chronic gut inflammation (Hampe et al., 2007; Prescott et al., 2007; Rioux et al., 2007). "
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    ABSTRACT: Innate immune responses are the first line of defense for an organism to restrict invading pathogens. They fulfill two main functions, namely detection of the pathogen to successively alarm the appropriate components of the immune system and early inhibition of the infection to prevent demise of the infected organism before a more tailored immune response, usually mediated by the adaptive immune system, can be mounted. Autophagy and phagocytosis, modified by the autophagic core machinery, contribute to these functions by regulating pathogen detection, influencing the production of innate immune mediators and directly restricting intracellular and extracellular pathogens as an effector mechanism of innate immunity. These aspects of the involvement of mainly macroautophagy in innate immune responses will be discussed in this review.
    Cellular Microbiology 09/2014; 16(11). DOI:10.1111/cmi.12358 · 4.92 Impact Factor
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