title: MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response.
abstract: In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-κB to induce type I interferons. [corrected] We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here, we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils that are capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Fajian
authors.initials: F
authors.lastname: Hou
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Brian
authors.initials: B
authors.lastname: Skaug
authors.forename: Qiu-Xing
authors.initials: QX
authors.lastname: Jiang
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D025821:Polyubiquitin / Q000378:metabolism; D011328:Prions / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D029082:Sendai virus; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D025821:Polyubiquitin; D011328:Prions; D018168:Receptors, Retinoic Acid; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; C512612:MAVS protein, mouse; C505371:MAVS protein, human