Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS‐STING and RIG‐I‐MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.

中文翻译：

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自身免疫基因 IRGM 抑制 cGAS-STING 和 RIG-I-MAVS 信号以控制干扰素反应。

1 型干扰素反应的激活与自身免疫性疾病的发病机制广泛相关。免疫相关 GTP 酶 M (IRGM) 的功能丧失也与几种自身免疫性疾病有关，但其作用机制尚不清楚。在这里，我们发现 IRGM 是干扰素反应的主要负调节剂。在 IRGM 敲除小鼠和人类细胞中，导致干扰素刺激的基因表达的几种核酸传感途径被高度激活。从机制上讲，我们表明 IRGM 与核酸传感器蛋白（包括 cGAS 和 RIG-I）相互作用，并介导它们的 p62 依赖性自噬降解以抑制干扰素信号传导。此外，IRGM 缺乏会导致有缺陷的线粒体自噬，从而导致释放细胞溶质 DAMP 和 mtROS 的失效泄漏线粒体的积累。因此，IRGM 缺乏不仅会增加传感器的水平，还会增加那些触发 cGAS-STING 和 RIG-I-MAVS 信号轴激活的刺激的水平，从而导致 IFN 反应的强烈诱导。总之，这项研究定义了 IRGM 维持干扰素稳态和预防自身免疫性疾病的分子机制。