What question did this study set out to answer?

Identify mechanisms by which STING acts as a barrier against influenza A virus (IAV) transmission in humans.

February 28, 2026Science0 citations

STING–NF-κB signaling builds an influenza spillover barrier

RYRunxin YeZhejiang University SWSongdi WangZhejiang University YHYuanming HuZhejiang Chinese Medical University

Key Points

Identify mechanisms by which STING acts as a barrier against influenza A virus (IAV) transmission in humans.
Demonstrated STING activation of NF-κB signaling pathway.
Analyzed the role of NF-κB-stimulated genes in IAV restriction.
Examined mutations in IAVs that evade STING activation.
Investigated specific interactions within the STING-NF-kB signaling pathway.
STING activation led to the expression of NSGs crucial for IAV restriction.
GADD34 was identified as a key protein in the restriction mechanism.
Some IAVs mutated to escape STING recognition, impacting replication efficiency.

Abstract

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.

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