Sarbecoviruses Suppress Innate Immunity by Recruiting PPM1A to Modulate STAT2 and ORF9b Phosphorylation.

Coronaviruses have persistently triggered global pandemics in the 21st century, featuring either high transmissibility or high pathogenicity. A hallmark of these infections is the delayed activation of innate immune responses, resulting in dysregulated antiviral signaling and uncontrolled viral replication. Multiple viral proteins and hijacked host proteins contribute to immune evasion, representing potential therapeutic targets. Here, we identify viral ORF9b as a conserved accessory protein across the Sarbecovirus subgenus that consistently suppresses innate immune responses by recruiting the protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A). Mechanistically, PPM1A exerts dual roles by directly dephosphorylating ORF9b and indirectly downregulating STAT2 phosphorylation, thereby suppressing RIG-I/MAVS and JAK-STAT signaling pathways. The PPM1A inhibitor SMIP-031 inhibits coronavirus replication and restores the antiviral innate immune homeostasis. These findings reveal a conserved immune-evasion strategy in sarbecoviruses and highlight the ORF9b-PPM1A axis as a potential target for broad-spectrum sarbecovirus therapeutics to help prevent future pandemics.