MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades

Abstract

RNA virus infections are detected by the RIG-I family of receptors, which induce type-I interferons through the mitochondrial protein MAVS. MAVS forms large prion-like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce interferons. Here we show that MAVS polymers recruit several TRAF proteins, including TRAF2, TRAF5, and TRAF6, through distinct TRAF-binding motifs. Mutations of these motifs that disrupted MAVS binding to TRAFs abrogated its ability to activate IRF3. IRF3 activation was also abolished in cells lacking TRAF2, 5, and 6. These TRAF proteins promoted ubiquitination reactions that recruited NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. These results delineate the mechanism of MAVS signaling and reveal that TRAF2, 5, and 6, which are normally associated with NF-κB activation, also play a crucial role in IRF3 activation in antiviral immune responses.DOI: http://dx.doi.org/10.7554/eLife.00785.001

A catalytic-independent role for the LUBAC in NF-κB activation upon antigen receptor engagement and in lymphoma cells

“…Moreover, TNFa-but not TCR-mediated NF-kB activation was boosted when the negative regulator of LUBAC catalytic activity OTULIN 20,21,24 was silenced (supplemental Figure 12). Last, plasmids that contain an shRNA against human HOIP followed by a RNAi-resistant HOIP wild type or a catalytically inactive mutant (C699S/C702S, 25 HOIP-CS) allowed us to simultaneously silence and reconstitute HOIP in cells. Although important for TNFa signaling, HOIP catalytic activity was dispensable for NF-kB activation upon TCR engagement ( Figure 1K; supplemental Figure 13).…”

WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines

“…Upon recognition, the conformation of RIG-I is changed and recruited to mitochondria by virus-induced signaling adaptor (VISA, also known as MAVS, IPS-1, and Cardif) (10)(11)(12)(13). The activated VISA then recruits mediator of IFN regulatory factor (IRF) 3 activation (MITA), TNFR-associated factor (TRAF) 3, and TRAF6 to the mitochondria and forms a huge signaling complex (1,7,8,(14)(15)(16). TRAF6 activates the IKK complex, which phosphorylates IkBa and activates NF-kB.…”

Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

“…21 The latest findings suggest that the activated MAVS is able to recruit and activate E3 ligases TRAF2, TRAF5, and TRAF6 to ubiquitinate TRAF2 and other proteins, which then through the adaptor NEMO recruit kinases -IKK and TBK1. 22 These kinases phosphorylate IκBα and IRF3, and therefore, activate the transcription factors-IRF3 and NFκB-to switch on the gene expression of IFN and cytokines. 11,21,22 As a subgroup of the Superfamily 2 (SF2) nucleic acid-dependent ATPases, RLRs contain a helicase core in the middle of the gene.…”

“…22 These kinases phosphorylate IκBα and IRF3, and therefore, activate the transcription factors-IRF3 and NFκB-to switch on the gene expression of IFN and cytokines. 11,21,22 As a subgroup of the Superfamily 2 (SF2) nucleic acid-dependent ATPases, RLRs contain a helicase core in the middle of the gene. 7 This core domain harbors the conserved structural and functional elements of Superfamily 1 and 2 (SF1 and SF2) nucleic acid-dependent ATPases: two RecA-like domains containing a set of conserved sequence features: motifs Q, (Fig.…”