Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production
Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production
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DOI：
10.1038/nature07383
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发表时间：
2008-11-13
期刊：
影响因子：
64.8
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
--
作者：
Saitoh, Tatsuya;Fujita, Naonobu;Akira, Shizuo
蛋白质降解系统对于严格控制炎症免疫反应至关重要(1,2)。自噬是一种批量降解系统，可将细胞质成分输送到自溶酶体中，控制长寿命蛋白质、不溶性蛋白质聚集体和入侵微生物的降解，并被认为参与炎症调节(3-5)。然而，自噬调节炎症反应的机制尚不清楚。在此，我们证明与克罗恩病 (6,7) 有关的 Atg16L1（自噬相关 16-like 1）可调节小鼠中内毒素诱导的炎症小体激活。 Atg16L1- 缺陷会破坏 Atg12-Atg5 缀合物向隔离膜的募集，导致微管相关蛋白 1 轻链 3 (LC3) 与磷脂酰乙醇胺缀合的损失。因此，Atg16L1 缺陷细胞中自噬体的形成和长寿命蛋白质的降解均受到严重损害。在用脂多糖（Toll 样受体 4 的配体）刺激后，Atg16L1 缺陷型巨噬细胞会产生大量炎症细胞因子 IL-1β 和 IL-18。在脂多糖刺激的巨噬细胞中，Atg16L1 缺陷会导致含有 Toll/IL-1 受体结构域的接头诱导 IFN-β (TRIF) 依赖性 caspase-1 激活，从而导致 IL-1 β 的产生增加。造血细胞中缺乏Atg16L1的小鼠对葡聚糖硫酸钠诱导的急性结肠炎高度敏感，注射抗IL-1β和IL-18抗体可以缓解这种情况，表明Atg16L1在抑制肠道炎症中的重要性。这些结果表明 Atg16L1 是自噬机制的重要组成部分，负责控制内毒素诱导的炎症免疫反应。
Systems for protein degradation are essential for tight control of the inflammatory immune response(1,2). 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 inflammation(3-5). 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 disease(6,7), 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-1 beta 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-1 beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium- induced acute colitis, which is alleviated by injection of anti-IL-1 beta 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.