MAVS self-association mediates antiviral innate immune signaling.
The innate immune system recognizes nucleic acids during viral infection and stimulates cellular antiviral responses. Intracellular detection of RNA virus infection is mediated by the RNA helicases RIG-I (retinoic acid inducible gene I) and MDA-5, which recognize viral RNA and signal through the adaptor molecule MAVS (mitochondrial antiviral signaling) to stimulate the phosphorylation and activation of the transcription factors IRF3 (interferon regulatory factor 3) and IRF7. Once activated, IRF3 and IRF7 turn on the expression of type I interferons, such as beta interferon. Interestingly, unlike other signaling molecules identified in this pathway, MAVS contains a C-terminal transmembrane (TM) domain that is essential for both type I interferon induction and localization of MAVS to the mitochondrial outer membrane. However, the role the MAVS TM domain plays in signaling remains unclear. Here we report the identification of a function for the TM domain in mediating MAVS self-association. The activation of RIG-I/MDA-5 leads to the TM-dependent dimerization of the MAVS N-terminal caspase recruitment domain, thereby providing an interface for direct binding to and activation of the downstream effector TRAF3 (tumor necrosis factor receptor-associated factor 3). Our results reveal a role for MAVS self-association in antiviral innate immunity signaling and provide a molecular mechanism for downstream signal transduction.
Tang
Eric D
ED
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, USA.
Wang
Cun-Yu
CY
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D011485:Protein Binding; D012328:RNA Viruses / Q000276:immunology*; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1