Natural Soluble Interleukin-15Rα Is Generated by Cleavage That Involves the Tumor Necrosis Factor-α-converting Enzyme (TACE/ADAM17)

• Published in: The Journal of biological chemistry 2004-09, Vol.279 (39), p.40368-40375
• Main Authors: Budagian, Vadim, Bulanova, Elena, Orinska, Zane, Ludwig, Andreas, Rose-John, Stefan, Saftig, Paul, Borden, Ernest C., Bulfone-Paus, Silvia
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M404125200

This study shows that the high affinity α-chain of the interleukin (IL)-15 receptor exists not only in membrane-anchored but also in soluble form. Soluble IL-15Rα (sIL-15Rα) can be detected in mouse sera and cell-conditioned media by enzyme-linked immunosorbent assay and by immunoprecipitation and Western blotting. This protein has a molecular mass of about 30 kDa because of the presence of a single N-glycosylation site, which is reduced to 26 kDa after N-glycosidase treatment. Transmembrane IL-15Rα is constitutively converted into its soluble form by proteolytic cleavage that involves tumor necrosis factor-α-converting enzyme (TACE), and this process is further enhanced by phorbol 12-myristate 13-acetate (PMA) stimulation. The hydroxamate GW280264X, which is capable of blocking TACE and the closely related disintegrin-like metalloproteinase 10 (ADAM10), effectively inhibited both spontaneous and PMA-inducible cleavage of IL-15Rα, whereas GI254023X, which preferentially blocks ADAM10, was ineffective. Overexpression of TACE but not ADAM10 in COS-7 cells enhanced the constitutive and PMA-inducible cleavage of IL-15Rα. Moreover, murine fibroblasts deficient in TACE but not ADAM10 expression exhibited a significant reduction in the spontaneous and inducible IL-15Rα shedding, whereas a reconstitution of TACE in these cells restored the release of sIL-15Rα, thereby suggesting that TACE-mediated proteolysis may represent a major mechanism for sIL-15Rα generation in mice. The existence of natural sIL-15Rα offers novel insights into the complex biology of IL-15 and envisages a new level for therapeutic intervention.