Nipah virus (NiV) and Hendra virus (HeV) are related, highly pathogenic, zoonotic viruses that use bats from the Pteropus genus as reservoir hosts. Both are classified as members of the henipavirus genus in the paramyxovirus family. The NiV-encoded W protein has been implicated as a virulence factor in ferret and non-human primate models. Recombinant Nipah virus (rNiV) unable to produce W shows a striking phenotype, with virulence shifting from the rapidly lethal pneumonia caused by wild-type virus to a more delayed yet still fatal viral encephalitis. One unique feature of W is its predominantly nuclear localization in most cell types and suppression of IFN responses by the TLR3-signaling associated protein TRIF has been shown to be impaired by mutations that disrupt W nuclear import. To mediate trafficking into the nucleus, there are seven human isoforms of importin α which mediate nuclear import of cargo in a tissue- and isoform-specific manner. How nuclear import adaptors differentially interact with viral cargo harbouring the same nuclear localisation signal (NLS) remains poorly understood, as the NLS recognition region is highly conserved. Here, we provide a structural basis for the nuclear import specificity of W proteins in Hendra and Nipah viruses. We determine the structural interfaces of these cargo bound to importin α1 and α3, identifying a 2.4-fold more extensive interface and > 50-fold higher binding affinity for importin α3. Through the design of importin α1 and α3 chimeric and mutant proteins, together with structures of cargo-free importin α1 and α3 isoforms, we establish that the molecular basis of specificity resides in the differential positioning of the armadillo repeats 7 and 8. Overall, this study provides mechanistic insights into viral:host interaction specificity which mediate nucleocytoplasmic transport and suppression of IFN responses. The work was published last year (Ref 1)