Antiviral function and viral antagonism of the rapidly evolving dynein activating adapter NINL

Viruses interact with the intracellular transport machinery to promote viral replication. Such host-virus interactions can drive host gene adaptation, leaving signatures of pathogen-driven evolution in host genomes. Here we leverage these genetic signatures to identify the dynein activating adaptor, ninein-like (NINL), as a critical component in the antiviral innate immune response and as a target of viral antagonism. Unique among genes en¬¬coding for dynein subunits, subunits of its co-factor dynactin, and dynein activating adaptors, NINL has evolved under recurrent positive selection, specifically in its carboxy-terminal cargo binding region. Consistent with a role for NINL in host immunity, NINL knockout cells are more permissive to viral replication as a result of a severe attenuation of interferon stimulated gene (ISG) production following interferon treatment. Moreover, we show that proteases encoded by diverse picornaviruses and coronaviruses cleave and disrupt NINL function in a host- and virus-specific manner. Our work reveals the importance of NINL in the antiviral response and the utility of using signatures of host-virus conflicts to uncover new components of antiviral immunity and targets of viral antagonism. Comparative gene expression analysis of RNA-seq data for A549 cells and its gene knockout derivatives (NINL KO, NIN KO) with or without interferon alpha treatment