In evolution’s unending race: ancestral STING sensors in Salmo salar mediate intracellular bacterial detection and programmed cell death through evolutionarily conserved pathways

Introduction:
“In evolution’s relentless race, survival hinges on constant adaptation—stagnation means extinction.” The Stimulator of Interferon Genes (STING) pathway exemplifies this principle, serving as a conserved cytosolic DNA sensor from Drosophila to salmon to humans. While well-characterized in mammals, the structural and functional roles of STING during intracellular bacterial infection in teleosts remain incompletely understood.
Methods:
We structurally characterized the ancestral STING ortholog from Atlantic salmon (Salmo salar) using AlphaFold-based modeling to identify conserved motifs, including the cyclic dinucleotide (CDN)-binding cleft and key phosphorylation sites. Molecular docking was used to assess the interaction between salmon STING and a validated human STING agonist. Transcriptomic profiling was performed on immune tissues and SHK-1 macrophage-like cells infected with Piscirickettsia salmonis to examine gene expression dynamics.
Results:
Structural modeling confirmed conservation of critical STING domains. Docking CF-102 agonist analysis showed high binding affinity between the human agonist and salmonid STING, supporting its potential cross-species utility. Transcriptomic data revealed robust sting1 expression in immune tissues and rapid upregulation post-infection. In SHK-1 cells, sting1, IFN-α, TNF-α, and IL-1β peaked at 4 hours post-infection (hpi), followed by a collapse in inflammatory signaling by 5 days post-infection (dpi), despite sustained sting1 transcription—suggesting functional uncoupling driven by immune evasion. In vivo, prolonged DDX41-STING activation correlated with suppression of pyroptosis, necroptosis, and inflammatory pathways, consistent with bacterial immune modulation.
Discussion:
These findings establish S. salar as a powerful model for dissecting STING biology and introduce the Evolutionary Molecular Immunity Race (EMIR) framework, where STING governs immune trajectories across hundreds of millions of years of vertebrate evolution, including the ~80-million-year diversification of the salmonid lineage.