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Molecular mechanism of viral RNA recognition and MDA5 activation through LGP2

Duic, Ivana 京都大学 DOI:10.14989/doctor.k23336

2021.03.23

概要

RIG-I, MDA5 and LGP2 belong to a family of RNA helicases (collectively termed as RIG-I-Like Receptor, RLR) functioning as a critical sensor for invading and replicating viral RNA. Upon sensing viral double stranded (ds)RNA, RLR triggers antiviral responses and promotes later acquired immunity against viruses. The central helicase domain is conserved in RLR and exhibits ATPase activity upon RNA binding. Genetic deletion analyses revealed that RIG-I and MDA5 sense short (<1,000 bp) and long (>1,000 bp) viral dsRNA, respectively. RIG-I and MDA5 share a N- terminal domain (Caspase Activation and Recruitment Domain, CARD), acting as a molecular switch for signaling. Crystal structure and molecular biological analyses suggest that CARD is masked in inactive state but exposed upon dsRNA detection. Although LGP2 lacks CARD, knockout studies suggest that it participates in the positive regulation by RIG-I and MDA5.

The applicant aimed to delineate the mechanism underlying viral dsRNA sensing by MDA5 and its cooperation with LGP2. MDA5 bound long dsRNA by forming a fiber like polymer along the length of dsRNA by atomic force microscope observation as reported previously by electron microscopic observation. In the presence of LGP2, the fiber formation was highly accelerated. By using molecular tag for LGP2, the applicant revealed that single LGP2 molecule was incorporated in every 5-9 MDA5 molecules in the polymer. Interestingly, the fiber dissociated upon addition of ATP. To analyze fiber formation and its dissociation, the applicant fractionated MDA5 fiber by size exclusion chromatography and revealed that the fiber dissociation was enhanced in the presence of both LGP2 and ATP. Next, to analyze CARD exposure in the fiber and the dissociated MDA5, the samples were subjected to limited trypsin digestion followed by SDS-PAGE analysis. By analyzing the digestion products, it was revealed that CARD of MDA5 was exposed upon dsRNA binding and the exposure was notably enhanced in the presence of LGP2. Furthermore, the dissociated MDA5/LGP2 complex by ATP hydrolysis was isolated and analyzed for CARD exposure. The result strongly suggested that MDA5 kept exposed CARD after dissociation from dsRNA, however CARD of non-activated MDA5 was masked. In summary, LGP2 is MDA5 nucleator, resulting in rapid viral RNA recognition by fiber formation. LGP2 is incorporated into the MDA5-RNA fiber. LGP2 enhances MDA5 conformational changes, promoting the exposure of CARD and dissociation through ATP hydrolysis. The conformational changes are preserved after dissociation from dsRNA and mediate efficient signal transduction in the cytoplasm.

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