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

• Published in: eLife Vol. 11
• Main Authors: Stevens, Donté Alexander, Beierschmitt, Christopher, Mahesula, Swetha, Corley, Miles R, Salogiannis, John, Tsu, Brian V, Cao, Bryant, Ryan, Andrew P, Hakozawki, Hiroyuki, Reck-Peterson, Samara L, Daugherty, Matthew D
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 12.10.2022; eLife Sciences Publications, Ltd
• Subjects: Antagonism; Antiviral Agents; Antiviral drugs; Coronaviruses; Dynein; Dyneins; Evolution; Genes; Genomes; host–virus evolution; Immune response; Immunity (Disease); Immunity, Innate; Immunology and Inflammation; Infections; innate antiviral immunity; Innate immunity; Interferon; Microbiology and Infectious Disease; microtubule-based transport; Pathogens; Proteins; Replication; viral antagonist; Viral infections; viral protease; Virus Replication; Viruses; dynein; microtubule-based transport; viral protease; host–virus evolution; viruses; infectious disease; inflammation; innate antiviral immunity; microbiology; viral antagonist; human; immunology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.81606

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 encoding components of active dynein complexes, NINL has evolved under recurrent positive (diversifying) selection, particularly in its carboxy-terminal cargo-binding region. Consistent with a role for NINL in host immunity, we demonstrate that NINL knockout cells exhibit an impaired response to interferon, resulting in increased permissiveness to viral replication. 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 genetic conflicts to uncover new components of antiviral immunity and targets of viral antagonism.