title: Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments.
abstract: The viral sensor MDA5 distinguishes between cellular and viral dsRNAs by length-dependent recognition in the range of ~0.5-7 kb. The ability to discriminate dsRNA length at this scale sets MDA5 apart from other dsRNA receptors of the immune system. We have shown previously that MDA5 forms filaments along dsRNA that disassemble upon ATP hydrolysis. Here, we demonstrate that filament formation alone is insufficient to explain its length specificity, because the intrinsic affinity of MDA5 for dsRNA depends only moderately on dsRNA length. Instead, MDA5 uses a combination of end disassembly and slow nucleation kinetics to "discard" short dsRNA rapidly and to suppress rebinding. In contrast, filaments on long dsRNA cycle between partial end disassembly and elongation, bypassing nucleation steps. MDA5 further uses this repetitive cycle of assembly and disassembly processes to repair filament discontinuities, which often are present because of multiple, internal nucleation events, and to generate longer, continuous filaments that more accurately reflect the length of the underlying dsRNA scaffold. Because the length of the continuous filament determines the stability of the MDA5-dsRNA interaction, the mechanism proposed here provides an explanation for how MDA5 uses filament assembly and disassembly dynamics to discriminate between self vs. nonself dsRNA.
authors.affiliation: Departments of Biological Chemistry and Molecular Pharmacology and Cell Biology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alys
authors.initials: A
authors.lastname: Peisley
authors.forename: Myung Hyun
authors.initials: MH
authors.lastname: Jo
authors.forename: Cecilie
authors.initials: C
authors.lastname: Lin
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: McGhee
authors.initials: M
authors.lastname: Orme-Johnson
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Sungchul
authors.initials: S
authors.lastname: Hohng
authors.forename: Sun
authors.initials: S
authors.lastname: Hur
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate / Q000502:physiology*; D000072640:Interferon-Induced Helicase, IFIH1; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D011485:Protein Binding; D011487:Protein Conformation; D012330:RNA, Double-Stranded / Q000276:immunology / Q000378:metabolism*; D012367:RNA, Viral / Q000276:immunology / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D012367:RNA, Viral; D000255:Adenosine Triphosphate; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1