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Identification and functional characterization of two CXCL17 paralogs from zebrafish
Jie Yu1, Wen-Feng Hu1, Juan-Juan Wang1
1Research Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
The Biochemical Journal
|January 12, 2026
Summary
Researchers identified two novel zebrafish C-X-C motif chemokine ligand 17 (CXCL17) paralogs, Dr-CXCL17 and Dr-CXCL17-like. These fish CXCL17s activate zebrafish G protein-coupled receptor 25 (GPR25), suggesting an ancient conserved signaling pathway.
Area of Science:
- Immunology
- Molecular Biology
- Evolutionary Biology
Background:
- The C-X-C motif chemokine ligand 17 (CXCL17) and its receptor G protein-coupled receptor 25 (GPR25) play key roles in mammalian immunity.
- Orthologs of CXCL17 have not been identified in non-mammalian vertebrates, limiting our understanding of this pathway's evolutionary history.
- Previous studies identified key structural motifs in mammalian CXCL17, including a C-terminal Xaa-Pro-Yaa motif, a signal peptide, and six cysteine residues.
Purpose of the Study:
- To identify and characterize non-mammalian orthologs of CXCL17 in zebrafish (Danio rerio).
- To investigate the functional interaction between identified zebrafish CXCL17 paralogs and zebrafish GPR25 (Dr-GPR25).
- To explore the evolutionary origins and conservation of the CXCL17-GPR25 signaling axis.
Main Methods:
- Bioinformatic analysis to identify potential CXCL17 paralogs in zebrafish based on conserved mammalian CXCL17 features.
- Recombinant protein expression in Escherichia coli, followed by in vitro refolding for Dr-CXCL17 and Dr-CXCL17-like.
- Functional assays including NanoBiT-based β-arrestin recruitment, ligand-receptor binding, and chemotaxis assays using transfected HEK293T cells.
Main Results:
- Two previously uncharacterized zebrafish CXCL17 paralogs, Dr-CXCL17 and Dr-CXCL17-like, were identified.
- Both Dr-CXCL17 and Dr-CXCL17-like demonstrated tight binding and activation of Dr-GPR25, inducing chemotactic responses.
- A conserved C-terminal tripeptide motif was found to be crucial for the function of both zebrafish CXCL17 paralogs.
Conclusions:
- The study successfully identified and functionally characterized the first non-mammalian CXCL17 orthologs in zebrafish.
- The findings indicate that the CXCL17-GPR25 pair is conserved in fish and likely originated in ancient fishes.
- This research provides a foundation for future studies on the role and evolution of the CXCL17-GPR25 pathway across vertebrate lineages.
