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.