Cell Host Microbe 24, 776–790 & 791–803 (2018)

Cytosolic RNA viruses are detected by the intracellular sensors RIG-I or MDA5, which both signal via the mitochondrial anti-viral signaling protein MAVS to initiate anti-viral immunity by inducing type I interferons and interferon-response gene expression. Two reports in Cell Host & Microbe identify distinct modes of post-translation regulation of MAVS. Li et al. show that MAVS is modified on Ser366 by O-linked-β-N-acetylglucosamine after viral infection. Such modification is required for K63-linked poly-ubiquitination and optimal activation of downstream TBK and NF-κB signaling pathways. Dai et al. show that the poly-ubiquitination of MAVS is negatively regulated by the host scaffold protein FAF1 through competition with the E3 ligase TRIM31. FAF1 is inactivated by phosphorylation by the kinase IKKε to derepress MAVS. Both pathways suggest that the poly-ubiquitination of MAVS is tightly regulated to prevent spurious or prolonged inflammatory responses.