An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response

• Published in: Nature communications 2015-07, Vol.6 (1), p.7811-7811, Article 7811
• Main Authors: Shi, Yuheng, Yuan, Bofeng, Qi, Nan, Zhu, Wenting, Su, Jingru, Li, Xiaoyan, Qi, Peipei, Zhang, Dan, Hou, Fajian
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/95; 38/22; 38/90; 631/250/255/2514; 631/250/262; 631/326/596/1296; 631/80/86; 82/80; 96/106; 96/35; 96/63; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Animals; Cell Line; DEAD Box Protein 58; DEAD-box RNA Helicases - immunology; Gene Knockout Techniques; HEK293 Cells; Humanities and Social Sciences; Humans; Immunity, Innate - immunology; Interferon Regulatory Factor-3 - immunology; Interferon Type I - immunology; Mice; multidisciplinary; NF-kappa B - immunology; Receptors, Immunologic; RNA, Viral - immunology; Science; Science (multidisciplinary); Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Vesiculovirus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8811

In response to virus infection, RIG-I senses viral RNA and activates the adaptor protein MAVS, which then forms prion-like filaments and stimulates a specific signalling pathway leading to type I interferon production to restrict virus proliferation. However, the mechanisms by which MAVS activity is regulated remain elusive. Here we identify distinct regions of MAVS responsible for activation of transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These IRF3- and NF-κB-stimulating regions recruit preferential TNF receptor-associated factors (TRAFs) for downstream signalling. Strikingly, these regions’ activities are inhibited by their respective adjacent regions in quiescent MAVS. Our data thus show that an autoinhibitory mechanism modulates MAVS activity in unstimulated cells and, on viral infection, individual regions of MAVS are released following MAVS filament formation to activate antiviral signalling cascades. The cellular protein RIG-I detects viral RNA and activates another protein, MAVS, which then forms filaments and stimulates an antiviral pathway. Here, the authors identify different regions within MAVS involved in activating transcription factors IRF3 and NF-κB, and in MAVS self-inhibition.