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J. Biol. Chem., Vol. 280, Issue 20, 19858-19866, May 20, 2005

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Recycling of the Membrane-anchored Chemokine, CX₃CL1^*

Guang-Ying Liu, Vathany Kulasingam, R. Todd Alexander, Nicolas Touret, Alan M. Fong, Dhavalkumar D. Patel, and Lisa A. Robinson¶

From the The Hospital for Sick Children Research Institute and the University of Toronto, Toronto M5G 1X8, Canada and Thurston Arthritis Research Center, The University of North Carolina, Chapel Hill, North Carolina 27599-7280

CX₃CL1 (fractalkine) plays an important role in inflammation by acting as both chemoattractant and as an adhesion molecule. As for other chemokines, expression of CX₃CL1 is known to be regulated at the level of transcription and translation. The unique transmembrane structure of CX₃CL1 raises the possibility of additional functional regulation by altering its abundance at the cell surface. This could be accomplished in principle by changes in traffic between subcellular compartments. To analyze this possibility we examined the subcellular distribution of CX₃CL1 in human ECV-304 cells stably expressing untagged or green fluorescent protein-tagged forms of the chemokine. CX₃CL1 was present in two distinct compartments, diffusely on the plasma membrane and in a punctate juxtanuclear compartment. The latter shared some features with, yet was distinct from the conventional endocytic pathway and may represent a specialized recycling subcompartment. Accordingly, surface CX₃CL1 was found to be in dynamic equilibrium with the juxtanuclear vesicular compartment. Intracellular CX₃CL1 co-localized with the SNARE (soluble N-ethylmaleimide factor attachment protein receptor) proteins syntaxin-13 and VAMP-3. Cleavage of VAMP-3 by tetanus toxin or impairment of syntaxin-13 function by expression of a dominant-negative allele inhibited the ability of internalized CX₃CL1 to traffic back to the plasma membrane. These data demonstrate the existence of a dynamic, SNARE-mediated recycling of CX₃CL1 from the cell surface to and from an endomembrane storage compartment. The intracellular storage depot may serve as a source of the chemokine that could be rapidly mobilized by stimuli.

Received for publication, November 19, 2004 , and in revised form, February 15, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Paediatrics, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-7654 (ext. 1745); Fax: 416-813-6271; E-mail: lisa.robinson{at}sickkids.ca.

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