Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.
Department of Microchemistry, Proteomics & Lipidomics, Genentech, South San Francisco, CA, USA.
Nat Immunol. 2018 Mar;19(3):246-254. doi: 10.1038/s41590-017-0042-6. Epub 2018 Jan 22.
Defective autophagy is linked to diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease (IBD). However, the mechanisms by which autophagy limits inflammation remain poorly understood. Here we found that loss of the autophagy-related gene Atg16l1 promoted accumulation of the adaptor TRIF and downstream signaling in macrophages. Multiplex proteomic profiling identified SQSTM1 and Tax1BP1 as selective autophagy-related receptors that mediated the turnover of TRIF. Knockdown of Tax1bp1 increased production of the cytokines IFN-β and IL-1β. Mice lacking Atg16l1 in myeloid cells succumbed to lipopolysaccharide-mediated sepsis but enhanced their clearance of intestinal Salmonella typhimurium in an interferon receptor-dependent manner. Human macrophages with the Crohn's disease-associated Atg16l1 variant T300A exhibited more production of IFN-β and IL-1β. An elevated interferon-response gene signature was observed in patients with IBD who were resistant to treatment with an antibody to the cytokine TNF. These findings identify selective autophagy as a key regulator of signaling via the innate immune system.
自噬缺陷与类风湿性关节炎、狼疮和炎症性肠病（IBD）等疾病有关。然而，自噬限制炎症的机制仍知之甚少。在这里，我们发现自噬相关基因 Atg16l1 的缺失促进了衔接蛋白 TRIF 和巨噬细胞中下游信号的积累。多重蛋白质组学分析鉴定出 SQSTM1 和 Tax1BP1 作为选择性自噬相关受体，介导 TRIF 的周转。Tax1bp1 的敲低增加了 IFN-β 和 IL-1β 的产生。骨髓细胞中缺乏 Atg16l1 的小鼠在脂多糖介导的败血症中死亡，但以干扰素受体依赖的方式增强了对肠道沙门氏菌 Typhimurium 的清除。具有克罗恩病相关 Atg16l1 变体 T300A 的人类巨噬细胞表现出更多的 IFN-β 和 IL-1β 的产生。在对细胞因子 TNF 的抗体治疗有抗性的 IBD 患者中观察到干扰素反应基因谱升高。这些发现确定了选择性自噬是先天免疫系统信号的关键调节剂。
