ArticlePLoS pathogens2025
Hnf4α integrates AIF and caspase 3/9 signaling to restrict single and coinfecting pathogens in teleosts.
Article in PLoS pathogens, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Hepatocyte nuclear factor 4 alpha (Hnf4α), a conserved nuclear receptor central to vertebrate liver development and metabolic regulation, emerges here as a pivotal immune regulator in teleosts against complex infectious threats. While its metabolic roles are well-established, Hnf4α's function in bacterial infection, viral infection, and bacterial-viral coinfection-major challenges in global aquaculture-remained uncharacterized. This study reveals that teleost Hnf4α acts as a dual-functional immune checkpoint, essential for combating Aeromonas salmonicida, grass carp reovirus (GCRV), and their coinfection. In in vivo zebrafish models, hnf4α-deficient larvae showed profound susceptibility, with survival rates reduced by 13.33-40% during infections, whereas gcHnf4α overexpression enhanced larval survival by 17.78-23.33% in single or coinfection scenarios. In vitro analyses in CIK cells demonstrated that gcHnf4α restricts A. salmonicida proliferation and GCRV replication through activation of a mitochondrial apoptotic program. Mechanistically, gcHnf4α forms a nuclear signaling complex with apoptosis-inducing factor (AIF) and caspases 3/9, driving a dual-dependent apoptotic pathway: (1) AIF-mediated caspase-independent nuclear apoptotic processes and (2) caspase 3/9-dependent cytoplasmic apoptotic execution. Confocal microscopy and co-immunoprecipitation validated direct interactions between gcHnf4α and these apoptotic effectors. Pharmacological inhibition of caspases 3/9 or AIF silencing abrogated gcHnf4α's protective effects, while ectopic caspase expression rescued survival deficits in hnf4α-deficient larvae. These findings establish Hnf4α as a conserved molecular nexus linking nuclear receptor signaling to apoptotic immunity, offering a novel strategy for aquacultural disease control. By targeting the AIF-caspase axis, Hnf4α enables efficient pathogen elimination, delineating it as a promising target for developing dual-action immunomodulators.
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