LRRC25 inhibits type I IFN signaling by targeting ISG15‐associated RIG‐I for autophagic degradation

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. Synopsis Upon RNA virus infection, LRRC25 recognizes ISG15‐associated immune receptor RIG‐I and facilitates its degradation via p62‐mediated selective autophagy, thereby limiting RIG‐I‐dependent type I interferon signaling. LRRC25 negatively regulates type I interferon signaling upon RNA virus infection. LRRC25 promotes autophagic degradation of RIG‐I in a p62‐dependent manner. ISG15 serves as a signal for LRRC25‐mediated RIG‐I degradation. The interaction between RIG‐I, ISG15 and LRRC25 forms a negative feedback loop to avoid prolonged immune activation upon viral infection. Graphical Abstract Upon RNA virus infection, LRRC25 recognizes ISG15‐associated immune receptor RIG‐I and facilitates its degradation via p62‐mediated selective autophagy, thereby limiting RIG‐I‐dependent type I interferon signaling.