Research
| Title： | Hnf4α integrates AIF and caspase 3/9 signaling to restrict single and coinfecting pathogens in teleosts |
|---|---|
| First author： | Yan, Dong; Tao, Min Hui; Wu, Xiao Man; Zhang, Jie; Li, Ming; Chang, Ming Xian |
| Journal： | PLOS PATHOGENS |
| Years： | 2025 |
| DOI： | 10.1371/journal.ppat.1013491 |
| Abstract： | Hepatocyte nuclear factor 4 alpha (Hnf4 alpha), 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, Hnf4 alpha's function in bacterial infection, viral infection, and bacterial-viral coinfection-major challenges in global aquaculture-remained uncharacterized. This study reveals that teleost Hnf4 alpha acts as a dual-functional immune checkpoint, essential for combating Aeromonas salmonicida, grass carp reovirus (GCRV), and their coinfection. In in vivo zebrafish models, hnf4 alpha-deficient larvae showed profound susceptibility, with survival rates reduced by 13.33-40% during infections, whereas gcHnf4 alpha overexpression enhanced larval survival by 17.78-23.33% in single or coinfection scenarios. In vitro analyses in CIK cells demonstrated that gcHnf4 alpha restricts A. salmonicida proliferation and GCRV replication through activation of a mitochondrial apoptotic program. Mechanistically, gcHnf4 alpha 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 gcHnf4 alpha and these apoptotic effectors. Pharmacological inhibition of caspases 3/9 or AIF silencing abrogated gcHnf4 alpha's protective effects, while ectopic caspase expression rescued survival deficits in hnf4 alpha-deficient larvae. These findings establish Hnf4 alpha 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, Hnf4 alpha enables efficient pathogen elimination, delineating it as a promising target for developing dual-action immunomodulators. |
