RNF167 mediates atypical ubiquitylation and degradation of RLRs via two distinct proteolytic pathways

RNF167 mediates atypical ubiquitylation and degradation of RLRs via two distinct proteolytic pathways

Blog Article

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 Interface PCA Board identify an E3 ubiquitin ligase, namely RNF167, as a negative regulator of RLR-triggered IFN signaling.Mechanistically, RNF167 facilitates both atypical K6- and 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 in CTD domains leads to proteasome-dependent degradation of Hair Colour Remover 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.