4.8 Article

Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1208618109

Keywords

antiviral; innate immunity; filament dynamics; helicase; viral RNA

Funding

  1. GlaxoSmithKline
  2. Creative Research Initiatives (Physical Genetics Laboratory) [2009-0081562]
  3. World Class University program of the National Research Foundation of Korea [R31-10032]
  4. Massachusetts Life Sciences Center
  5. Pew Scholarship
  6. National Research Foundation of Korea [2009-0081562, R31-2012-000-10032-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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The viral sensor MDA5 distinguishes between cellular and viral dsRNAs by length-dependent recognition in the range of similar to 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.

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