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Human enteroviruses possess various mechanisms to suppress the host type I interferon (IFN) response in infected cells to establish viral replication. In the present study, we found that the enteroviral 3D\n            <jats:sup>pol<\/jats:sup>\n            protein (or RdRP), which is a viral RNA-dependent RNA polymerase for replicating viral RNA, plays a role in the inhibition of MDA5-mediated beta interferon (IFN-\u03b2) promoter activation. We further demonstrated that enteroviral 3D\n            <jats:sup>pol<\/jats:sup>\n            protein interacts with the caspase activation and recruitment domains (CARDs) of MDA5. 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