The RIG‐I‐like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that leucine‐rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR‐mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15‐associated RIG‐I to promote interaction between RIG‐I and the autophagic cargo receptor p62 and to mediate RIG‐I degradation via selective autophagy. Depletion of either LRRC25 or ISG15 abrogates RIG‐I‐p62 interaction as well as the autophagic degradation of RIG‐I. Collectively, our findings identify a previously unrecognized role of LRRC25 in type I IFN signaling activation by which LRRC25 acts as a secondary receptor to assist RIG‐I delivery to autophagosomes for degradation in a p62‐dependent manner.

RIG-I 样受体 (RLR) 对于防止 RNA 病毒感染至关重要，必须严格控制其活性以维持免疫稳态。在此，我们报道富含亮氨酸重复序列的蛋白 25 (LRRC25) 是 RLR 介导的 I 型干扰素 (IFN) 信号传导的关键负调节因子。 RNA 病毒感染后，LRRC25 特异性结合 ISG15 相关 RIG-I，促进 RIG-I 与自噬货物受体 p62 之间的相互作用，并通过选择性自噬介导 RIG-I 降解。 LRRC25 或 ISG15 的耗尽会消除 RIG-I-p62 相互作用以及 RIG-I 的自噬降解。总的来说，我们的研究结果确定了 LRRC25 在 I 型 IFN 信号传导激活中以前未被认识的作用，LRRC25 充当次级受体，协助 RIG-I 递送至自噬体，以 p62 依赖性方式降解。