Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10
Copyright policy )Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10
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.
- St. Michael's Hospital Canada
- Western University Canada
- Hospital for Sick Children Canada
- University of Toronto Canada
- Unity Health Toronto Canada
Chemokine CX3CL1, Tumor Necrosis Factor-alpha, Cell Membrane, Membrane Proteins, Videotape Recording, Articles, Endocytosis, ADAM Proteins, ADAM10 Protein, Actin Cytoskeleton, Luminescent Proteins, Microscopy, Fluorescence, Proteolysis, Human Umbilical Vein Endothelial Cells, Humans, Amyloid Precursor Protein Secretases, Cells, Cultured, Protein Binding
Chemokine CX3CL1, Tumor Necrosis Factor-alpha, Cell Membrane, Membrane Proteins, Videotape Recording, Articles, Endocytosis, ADAM Proteins, ADAM10 Protein, Actin Cytoskeleton, Luminescent Proteins, Microscopy, Fluorescence, Proteolysis, Human Umbilical Vein Endothelial Cells, Humans, Amyloid Precursor Protein Secretases, Cells, Cultured, Protein Binding
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