STING–NF-κB signaling builds an influenza spillover barrier

Influenza pandemics are often traced back to the spillover of avian influenza A viruses (IAVs) to humans. However, barriers against IAV transmission remain elusive. We demonstrated human stimulator of interferon genes (STING) as a transmission barrier against IAVs. STING activated nuclear factor κB (NF-κB) and downstream NF-κB–stimulated genes (NSGs) through a specific domain. Among these NSGs, growth arrest and DNA damage–inducible protein 34 ( GADD34 ) was crucial for IAV restriction. Some IAVs have evolved to evade activating human STING by mutating residue 115 in their matrix protein 1 (M1), which is essential for efficient viral replication in human respiratory cells. This barrier against the zoonotic threat of IAVs provides a tool for future investigations into the biological functions of the cyclic guanosine monophosphate–adenosine monosphosphate (cGMP-AMP) synthase (cGAS)–STING–NF-κB signaling pathway.