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, <i>growth arrest and DNA damage-inducible protein 34</i> (<i>GADD34</i>) 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.