Functional adhesiveness of the CX3CL1 chemokine requires its aggregation. Role of the transmembrane domain.

Abstract : In its native form, the chemokine CX3CL1 is a firmly adhesive molecule promoting leukocyte adhesion and migration and hence involved, along with its unique receptor CX3CR1, in various inflammatory processes. Here we investigated the role of molecular aggregation in the CX3CL1 adhesiveness. Assays of bioluminescence resonance energy transfer (BRET) and homogeneous time-resolved fluorescence (HTRF) in transfected cell lines and in primary cells showed specific signals indicative of CX3CL1 clustering. Truncation experiments showed that the transmembrane domain played a central role in this aggregation. A chimera with mutations of the 12 central transmembrane domain residues had significantly reduced BRET signals and characteristics of a non-clustering molecule. This mutant was weakly adhesive according to flow and dual pipette adhesion assays and was less glycosylated than CX3CL1, although, as we demonstrated, loss of glycosylation did not affect the CX3CL1 adhesive potency. We postulate that cell surfaces express CX3CL1 as a constitutive oligomer and that this oligomerization is essential for its adhesive potency. Inhibition of CX3CL1 self-assembly could limit the recruitment of CX3CR1-positive cells and may be a new pathway for anti-inflammatory therapies.
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Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2008, 283 (44), pp.30225-34. 〈10.1074/jbc.M802638200〉
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Patricia Hermand, Frédéric Pincet, Stéphanie Carvalho, Hervé Ansanay, Eric Trinquet, et al.. Functional adhesiveness of the CX3CL1 chemokine requires its aggregation. Role of the transmembrane domain.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2008, 283 (44), pp.30225-34. 〈10.1074/jbc.M802638200〉. 〈inserm-00392456〉

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