Article

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: 41.46). 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.

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Available from: Masaaki Komatsu
    • "Autophagy has many biological effects that include immunological processes and inflammation (Ma et al., 2013; Mathew et al., 2014; Deretic et al., 2015). One aspect of this role of autophagy is regulation of inflammasome activity (Schroder and Tschopp, 2010), whereby autophagy antagonizes inflammasome activation, through several proposed mechanisms (Saitoh et al., 2008; Nakahira et al., 2011; Zhou et al., 2011; Shi et al., 2012) that are, however, not fully understood. Another distinct manifestation is autophagic suppression of type I IFN responses through STING and RIG-I (retinoic acid-inducible gene 1)–like receptors (Jounai et al., 2007; Saitoh et al., 2009; Tal et al., 2009; Konno et al., 2013; Liang et al., 2014; Deretic et al., 2015) . "
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    ABSTRACT: The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.
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    • "This augmented autophagy may restrict the inflammatory response through reduced expression or increased degradation of proinflammatory cytokines such as interleukin (IL)-1b (Saitoh et al., 2008; Harris et al., 2011). In support of this, inhibition of autophagy augments TLR stimulated IL-1b expression (Saitoh et al., 2008 ). Furthermore, global haplodeficiency of Atg7 in obese mice causes insulin resistance with concomitant increases in lipid-associated inflammation and maturation of pro-IL-1b to IL-1b (Lim et al., 2014). "
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    ABSTRACT: Autophagy functions to degrade and recycle intracellular proteins and damaged organelles, maintaining the normal cellular function. Autophagy has been shown to play an important role in regulating normal function of pancreatic β cells and insulin-target tissues, such as skeletal muscle, liver, and adipose tissue. Enhanced autophagy also acts as a protective mechanism against oxidative stress in these tissues. Altered autophagic activity has been implicated in the progression of obesity to type 2 diabetes through impaired β-cell function and development of insulin resistance. In this review, we outline the normal regulation of autophagy in β cells and insulin target tissues and explore the dysregulation of autophagy in diabetic animal models and human subjects with type 2 diabetes. Furthermore, we highlight the role of impaired autophagy in the pathophysiology of diabetic complications, including nephropathy and cardiomyopathy. Finally, we summarize how autophagy might be targeted as a therapeutic option in type 2 diabetes.
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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.
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