PUBLICATION
Hnf4α integrates AIF and caspase 3/9 signaling to restrict single and coinfecting pathogens in teleosts
- Authors
- Yan, D., Tao, M.H., Wu, X.M., Zhang, J., Li, M., Chang, M.X.
- ID
- ZDB-PUB-250909-11
- Date
- 2025
- Source
- PLoS pathogens 21: e1013491e1013491 (Journal)
- Registered Authors
- Chang, Mingxian
- Keywords
- none
- MeSH Terms
-
- Animals
- Fish Diseases*/immunology
- Fish Diseases*/metabolism
- Fish Diseases*/microbiology
- Fish Diseases*/virology
- Reoviridae
- Zebrafish
- Coinfection*/immunology
- Caspase 9*/metabolism
- Hepatocyte Nuclear Factor 4*/genetics
- Hepatocyte Nuclear Factor 4*/immunology
- Hepatocyte Nuclear Factor 4*/metabolism
- Signal Transduction
- Carps
- Reoviridae Infections*/immunology
- Reoviridae Infections*/metabolism
- Reoviridae Infections*/veterinary
- Caspase 3/metabolism
- Aeromonas salmonicida/immunology
- Apoptosis
- Apoptosis Inducing Factor*/metabolism
- PubMed
- 40920830 Full text @ PLoS Pathog.
Citation
Yan, D., Tao, M.H., Wu, X.M., Zhang, J., Li, M., Chang, M.X. (2025) Hnf4α integrates AIF and caspase 3/9 signaling to restrict single and coinfecting pathogens in teleosts. PLoS pathogens. 21:e1013491e1013491.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping