Skip to main content

Research Repository

Advanced Search

CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans

White, Carl W.; Platt, Simon; Kilpatrick, Laura E.; Dale, Natasha; Abhayawardana, Rekhati S.; Dekkers, Sebastian; Kindon, Nicholas D.; Kellam, Barrie; Stocks, Michael J.; Pfleger, Kevin D. G.; Hill, Stephen J.

Authors

Carl W. White

Simon Platt

Rekhati S. Abhayawardana

Sebastian Dekkers

Nicholas D. Kindon

Profile image of BARRIE KELLAM

BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry

MICHAEL STOCKS MICHAEL.STOCKS@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry and Drug Discovery

Kevin D. G. Pfleger

STEPHEN HILL STEVE.HILL@NOTTINGHAM.AC.UK
Professor of Molecular Pharmacology



Abstract

CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)–based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.

Citation

White, C. W., Platt, S., Kilpatrick, L. E., Dale, N., Abhayawardana, R. S., Dekkers, S., Kindon, N. D., Kellam, B., Stocks, M. J., Pfleger, K. D. G., & Hill, S. J. (2024). CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans. Science Signaling, 17(828), Article abl3758. https://doi.org/10.1126/scisignal.abl3758

Journal Article Type Article
Acceptance Date Feb 29, 2024
Online Publication Date Mar 19, 2024
Publication Date Mar 19, 2024
Deposit Date Mar 20, 2024
Publicly Available Date Mar 26, 2024
Journal Science Signaling
Print ISSN 1945-0877
Electronic ISSN 1937-9145
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 17
Issue 828
Article Number abl3758
DOI https://doi.org/10.1126/scisignal.abl3758
Keywords Cell Biology; Molecular Biology; Biochemistry
Public URL https://nottingham-repository.worktribe.com/output/32745873
Publisher URL https://www.science.org/doi/10.1126/scisignal.abl3758
Additional Information This is the authors' version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on 19 Mar 2024, DOI: 10.1126/scisignal.abl3758

Files





You might also like



Downloadable Citations