MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades.
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.
Department of Molecular Biology , University of Texas Southwestern Medical Center , Dallas , United States.
Siqi
S
Liu
Jueqi
J
Chen
Xin
X
Cai
Jiaxi
J
Wu
Xiang
X
Chen
You-Tong
YT
Wu
Lijun
L
Sun
Zhijian J
ZJ
Chen
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008969:Molecular Sequence Data; D058105:Polymerization; D011485:Protein Binding; D029082:Sendai virus / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C491731:IKBKG protein, human; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase
Human; MAVS; Mouse; Viruses; innate immunity; mitochondria; signaling; ubiquitin; virus