RNF144B negatively regulates antiviral immunity by targeting MDA5 for autophagic degradation

As a RIG-I-like receptor, MDA5 plays a critical role in antiviral innate immunity by acting as a cytoplasmic double-stranded RNA sensor capable of initiating type I interferon pathways. Here, we show that RNF144B specifically interacts with MDA5 and promotes K27/K33-linked polyubiquitination of MDA5 at lysine 23 and lysine 43, which promotes autophagic degradation of MDA5 by p62. Rnf144b deficiency greatly promotes IFN production and inhibits EMCV replication in vivo. Importantly, Rnf144b-/- mice has a significantly higher overall survival rate than wild-type mice upon EMCV infection. Collectively, our results identify RNF144B as a negative regulator of innate antiviral response by targeting CARDs of MDA5 and mediating autophagic degradation of MDA5. MDA5 is a critical cytoplasmic RNA sensor capable of triggering type I interferon pathways. This study shows that the E3 ubiquitin ligase RNF144B suppresses innate antiviral responses via ubiquitination of MDA5.RNF144B is upregulated during RNA virus infection.RNF144B Promotes K27- and K33-linked ubiquitination of MDA5 at residues K23 and K43.Polyubiquitinated MDA5 is recognized by p62 and delivered to autophagosomes for degradation.RNF144B inhibits innate antiviral immune responses in vitro and in vivo and thereby enhances viral replication. MDA5 is a critical cytoplasmic RNA sensor capable of triggering type I interferon pathways. This study shows that the E3 ubiquitin ligase RNF144B suppresses innate antiviral responses via ubiquitination of MDA5.