Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo.

Abstract

The two known isoforms of IL-15 contain either a long signal peptide (LSP) or a short signal peptide (SSP), and are produced by alternatively spliced transcripts. It has been proposed that SSP IL-15 remains exclusively intracellular, and its function is unclear. In this study, we show that, similar to LSP IL-15, the SSP IL-15 is stabilized and secreted efficiently upon coexpression of IL-15Ralpha. Coinjection of SSP IL-15- and IL-15Ralpha-expressing plasmids into mice resulted in increased plasma levels of bioactive heterodimeric IL-15 and mobilization and expansion of NK and T cells. Therefore, SSP IL-15 is secreted and bioactive when produced as a heterodimer with IL-15Ralpha in the same cell. The apparent t(1/2) of this heterodimer is lower compared with LSP IL-15/IL-15Ralpha, due to different intracellular processing. Coexpression of both LSP IL-15 and SSP IL-15 in the presence of IL-15Ralpha results in lower levels of bioactive IL-15, indicating that LSP and SSP IL-15 compete for the binding to IL-15Ralpha when expressed in the same cell. Because the SSP IL-15 interaction to IL-15Ralpha leads to a complex with lower apparent stability, SSP IL-15 functions as competitive inhibitor of LSP IL-15. The data suggest that usage of alternative splicing is an additional level of control of IL-15 activity. Expression of both SSP and LSP forms of IL-15 appears to be conserved in many mammals, suggesting that SSP may be important for expressing a form of IL-15 with lower magnitude or duration of biological effects.

DOI: 10.4049/jimmunol.0900693
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@article{Bergamaschi2009SecretionAB, title={Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo.}, author={Cristina Bergamaschi and Rashmi Jalah and Viraj Kulkarni and Margherita Rosati and Gen-mu Zhang and Candido Alicea and Andrei S. Zolotukhin and Barbara K. Felber and George N. Pavlakis}, journal={Journal of immunology}, year={2009}, volume={183 5}, pages={3064-72} }