Abstract The precise regulation of the RIG-I-like receptors (RLRs)-mediated type I interferon (IFN-I) activation is crucial in antiviral immunity and maintaining host immune homeostasis in the meantime.Here, we identify an E3 ubiquitin ligase, namely RNF167, as a negative regulator of RLR-triggered IFN signaling.Mechanistically, RNF167 facilitates both atypical K6- and girls tees K11-linked polyubiquitination of RIG-I/MDA5 within CARD and CTD domains, respectively, which leads to degradation of the viral RNA sensors through dual proteolytic pathways.RIG-I/MDA5 conjugated with K6-linked ubiquitin chains in CARD domains is recognized by the autophagy cargo adaptor p62, that delivers the substrates to autolysosomes for selective autophagic degradation.In contrast, K11-linked polyubiquitination Mounts in CTD domains leads to proteasome-dependent degradation of RLRs.
Thus, our study clarifies a function of atypical K6- and K11-linked polyubiquitination in the regulation of RLR signaling.We also unveil an elaborate synergistic effect of dual proteolysis systems to control amplitude and duration of IFN-I activation, hereby providing insights into physiological roles of the cross-talk between these two protein quality control pathways.