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.

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., …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