MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors

We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-κB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria.These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.Upon infection, viruses are rapidly recognized by the innate immune system through germ line-encoded pattern-recognition receptors (PRRs) [1]. Several classes of PRR, including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), recognize viral components and directly activate immune cells. The RLRs are comprised of RIG-I and MDA-5 (melanoma differentiation-associated gene-5) that are cytosolic helicases sensing viral RNA [2]. Importantly, RIG-I and MDA-5 contain two CARDs (Caspase Activation and Recruitment Domains) [1,2]. The ATPase activity of both helicases as a result of binding to their ligands is required for conformational changes that lead to the exposure of the CARDs otherwise masked by the C-terminal regulatory domain. This conformational change is required for a putative interaction with the CARD domain of the mitochondrial adaptor MAVS (also known as IPS-1, Cardif or VISA) [3-6]. MAVS then activates two cytosolic protein kinase complexes, one consisting of the "noncanonical" IKK-related kinase TBK1 (TANK-binding kinase 1) or IKK-i/ε (inducible IκB kinase) associated with various adaptor proteins like TANK (TRAF family member associated NF-κB activator), NAP1 (NAK-associated protein 1) and NEMO (NF-κB Essential MOdulator), and the other comprising IKKα