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

Autor:	White CW; Cell Signalling and Pharmacology Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.; Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.; Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, Victoria, Australia.; Dimerix Limited, Melbourne, Victoria, Australia., Platt S; Cell Signalling and Pharmacology Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK., Kilpatrick LE; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.; School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK., Dale N; Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.; Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, Victoria, Australia., Abhayawardana RS; Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.; Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, Victoria, Australia., Dekkers S; Cell Signalling and Pharmacology Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.; School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK., Kindon ND; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.; School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK., Kellam B; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.; School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK., Stocks MJ; School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK., Pfleger KDG; Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.; Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, Victoria, Australia.; Dimerix Limited, Melbourne, Victoria, Australia., Hill SJ; Cell Signalling and Pharmacology Research Group, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2024 Mar 19; Vol. 17 (828), pp. eabl3758. Date of Electronic Publication: 2024 Mar 19.
DOI:	10.1126/scisignal.abl3758
Abstrakt:	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.
Databáze:	MEDLINE
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