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Mol Biol Cell. 2014 Dec 1;25(24):3884-99. doi: 10.1091/mbc.E13-11-0633. Epub 2014 Sep 24.

Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10.

Author information

1
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
3
Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5C1, Canada.
4
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
5
Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada Department of Paediatrics, University of Toronto, Toronto, ON M5S 2J7, Canada lisa.robinson@sickkids.ca.

Abstract

CX3CL1 is a unique chemokine that acts both as a transmembrane endothelial adhesion molecule and, upon proteolytic cleavage, a soluble chemoattractant for circulating leukocytes. The constitutive release of soluble CX3CL1 requires the interaction of its transmembrane species with the integral membrane metalloprotease ADAM10, yet the mechanisms governing this process remain elusive. Using single-particle tracking and subdiffraction imaging, we studied how ADAM10 interacts with CX3CL1. We observed that the majority of cell surface CX3CL1 diffused within restricted confinement regions structured by the cortical actin cytoskeleton. These confinement regions sequestered CX3CL1 from ADAM10, precluding their association. Disruption of the actin cytoskeleton reduced CX3CL1 confinement and increased CX3CL1-ADAM10 interactions, promoting the release of soluble chemokine. Our results demonstrate a novel role for the cytoskeleton in limiting membrane protein proteolysis, thereby regulating both cell surface levels and the release of soluble ligand.

PMID:
25253723
PMCID:
PMC4244198
DOI:
10.1091/mbc.E13-11-0633
[Indexed for MEDLINE]
Free PMC Article

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