Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine

Fractalkine (FK, CX3CL1) is a novel multidomain protein expressed on the su rface of endothelial cells. As a full-length transmembrane protein, FK bind s cells expressing CX3CR1, its cognate receptor, with high affinity. Proteo lytic cleavage of FK releases a soluble form that is a potent chemoattracta nt for monocytes, T cells, and natural killer cells. Activation of protein kinase C dramatically increases the rate of this cleavage. Regulation of FK cleavage is critical for maintaining the balance between the immobilized a nd soluble forms, but the protease responsible has not been identified. Her e we report that tumor necrosis factor-alpha -converting enzyme (TACE) is p rimarily responsible for the inducible cleavage of FK. After transfection i nto host cells, the proteolytic cleavage of FK was blocked by TACE-specific inhibitors and was not detected in cells genetically altered to remove TAL E activity. In contrast, the constitutive cleavage of FK was not mediated b y TALE and proceeded normally in TALE-null fibroblasts. We conclude that TA LE is primarily responsible for the inducible cleavage of FK. These studies identify a potentially important link between local generation of potent c ytokines and control of the balance between the cell adhesion and chemotact ic properties of FK.