MORC3 Is a Target of the Influenza A Viral Protein NS1

Microrchidia 3 (MORC3), a human ATPase linked to several autoimmune disorders, has been characterized both as a negative and positive regulator of influenza A virus. Here, we report that the CW domain of MORC3 (MORC3-CW) is targeted by the C-terminal tail of the influenza H3N2 protein NS1. The crystal structure of the MORC3-CW:NS1 complex shows that NS1 occupies the same binding site in CW that is normally occupied by histone H3, a physiological ligand of MORC3-CW. Comparable binding affinities of MORC3-CW to H3 and NS1 peptides and to the adjacent catalytic ATPase domain suggest that the viral protein can compete with the host histone for the association with CW, releasing MORC3 autoinhibition and activating the catalytic function of MORC3. Our structural, biochemical, and cellular analyses suggest that MORC3 might affect the infectivity of influenza virus and therefore has a role in cell immune response. [Display omitted] •MORC3 ATPase is a new target of NS1 from H3N2-subtype influenza virus•NS1 interacts with the CW domain of MORC3•NS1 occupies the histone-binding site of CW in the MORC3-CW:NS1 complex structure•Overexpression of MORC3 affects the infectivity of the H3N2-subtype influenza virus Influenza virus employs multiple mechanisms to hijack host cellular pathways and evade innate immune responses. Zhang et al. identified MORC3 ATPase as a new target of H3N2-subtype influenza A protein NS1.