A teleost-specific oxygen-immunity axis where FIH activates NF-κB via competitive IκBα binding - PubMed
5 hours ago
- #teleost immunity
- #NF-κB activation
- #oxygen-immunity axis
- Researchers identified a teleost-specific oxygen-immunity axis where the oxygen sensor FIH activates the NF-κB pathway by competitively displacing p65 from IκBα, independent of its hydroxylase activity.
- In vitro studies showed FIH binding to IκBα promotes p65 nuclear translocation and increases inflammatory gene expression; FIH knockdown blunted these responses.
- CRISPR/Cas9-generated drfih-/- zebrafish exhibited reduced NF-κB-driven inflammation, altered LPS responses, and a dose-dependent trade-off in Vibrio anguillarum infection—reduced resistance at low dose but mitigated immunopathology at high dose.
- Structural modeling and mutational analyses pinpointed a competitive interface; human FIH bound IκBα but did not activate NF-κB unless a C-terminal segment of human IκBα was replaced with the teleost version.
- Cross-species predictions revealed the competitive interface exists in several aquatic vertebrates, an amphibian, and a shrimp, but not in examined terrestrial species, suggesting lineage-specific adaptation linking oxygen sensing to innate immunity.