Résumé
SignificanceThe human restriction factor Myxovirus resistance 1 (MX1) presents an unusually broad antiviral activity against many different viruses, including influenza A virus (IAV), but its mechanism of action remains elusive. Hence, despite massively inhibiting IAV replication, MX1 has never been shown to colocalize with any IAV components, and no MX1 functional cellular cofactors are known. Here, we show that MX1 transiently associates in the cytoplasm with neosynthesized viral ribonucleoproteins and, using dynein, reroutes them toward the microtubule organizing center where they remain sequestered. These findings reveal a previously uncharacterized antiviral strategy, clarifying the activity of MX1 and identifying dynein as a functional cofactor, thereby advancing our understanding of natural cellular defenses against viruses.
Interferon-inducible Myxovirus resistance 1 (MX1) proteins are known to restrict influenza A virus (IAV) transcription/replication process. Herein, we show that this early restriction was only partial against human IAVs, with later replication stages more strongly inhibited. Murine (Mm)Mx1 induced an abnormal nuclear accumulation of the viral nucleoprotein (NP) at late time points postinfection. This block was observed to a lower extent with human (Hs)MX1; however, HsMX1 strongly impacted cytoplasmic trafficking of de novo synthesized viral ribonucleoprotein complexes (vRNPs). Indeed, live imaging experiments revealed a transient association of HsMX1 with Rab11a-associated vRNPs, which induced their clustering and their dynein-dependent retrograde transport toward the microtubule organizing center (MTOC). There, vRNPs remained sequestrated together with cellular cofactors YBX1 and Rab11a in large clusters, while MX1 dissociated from them. Dynein inhibition prevented the vRNP clustering and sequestration and significantly rescued infectious IAV production in the presence of HsMX1. In conclusion, this study provides evidence of IAV vRNPs being rerouted and accumulated away from the plasma membrane through the coordinated action of HsMX1 restriction factor, dynein, and the microtubule network.