The RNA-splicing ligase RNA 2′,3′-cyclic phosphate and 5′-OH ligase (RTCB) is a catalytic subunit of the tRNA-splicing ligase complex, which plays an essential role in catalyzing tRNA splicing and modulating the unfolded protein response. However, the function of RTCB in influenza A virus (IAV) replication has not yet been described. In this study, RTCB was revealed to be an IAV-suppressed host factor that was significantly downregulated during influenza virus infection in several transformed cell lines, as well as in primary human type II alveolar epithelial cells, and its knockout impaired the propagation of the IAV. Mechanistically, RTCB depletion led to a robust elevation in the levels of type I and type III IFNs and proinflammatory cytokines in response to IAV infection, which was confirmed by RTCB overexpression studies. Lastly, RTCB was found to compete with DDX21 for RNA helicase DDX1 binding, attenuating the DDX21-DDX1 association and thus suppressing the expression of IFN and downstream IFN-stimulated genes. Our study indicates that RTCB plays a critical role in facilitating IAV replication and reveals that the RTCB-DDX1 binding interaction is an important innate immunomodulator for the host to counteract viral infection.

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