The conserved poxvirus membrane entry-fusion apparatus component OPG147 targets MITA/STING for immune evasion.

Monkeypox virus (MPXV) causes severe diseases in immunocompromised individuals. How MPXV evades the host defense remain enigmatic. We performed expression screens and identified MPXV OPG147, a membrane fusion machinery protein, as an inhibitor of cGAS-MITA/STING-mediated innate immunity. OPG147 from other poxviruses including the prototypic vaccinia virus (VACV) shows similar functions. OPG147 is associated with MITA/STING and STIM1, a calcium sensor that retains MITA/STING in the ER. OPG147 does not block cGAMP binding to MITA, but inhibits its ISGylation, dimerization/oligomerization and trafficking, thereby suppressing its activation. Mutation of VACV OPG147 F55/T116/T117 to alanine (VACVOPG147/3A) has no effects on its infection and replication, but induces higher innate immune response compared with wild-type VACV in cells and mice. VACVOPG147/3A infection also results in lower viral loads and decreased disease severity in mice. Our findings suggest that OPG147 contributes to immune evasion and is a virulence factor of poxviruses.