The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.

中文翻译：

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RIPosomes 的选择性自噬在细菌感染期间维持先天免疫稳态

NOD1/2-RIPK2 是一种关键的胞质信号复合物，可激活 NF-κB 促炎症反应，对抗入侵的病原体。然而，不受控制的 NF-κB 信号传导可能会导致组织损伤，从而导致慢性疾病。NODs-RIPK2-NF-κB 先天免疫轴激活和分解的机制仍知之甚少。在这里，我们证明细菌感染会诱导内源性 RIPK2 寡聚物 (RIPosomes) 的形成，这些寡聚物是自组装实体，覆盖细菌以诱导 NF-κB 反应。接下来，我们证明自噬蛋白 IRGM 和 p62/SQSTM1 与 NOD1/2、RIPK2 和 RIPosomes 发生物理相互作用，以促进其选择性自噬并限制 NF-κB 激活。IRGM 抑制由志贺氏菌和沙门氏菌诱导的 RIPK2 依赖性促炎程序。一致地，治疗性抑制 RIPK2 可改善Irgm1 KO 小鼠中志贺氏菌感染和 DSS 诱导的肠道炎症。这项研究确定了一种独特的机制，即先天免疫蛋白和自噬机制被招募到细菌中以进行防御并维持免疫稳态。