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Secretion and Biological Activity of Short Signal Peptide IL-15 Is Chaperoned by IL-15 Receptor Alpha In Vivo¹

Cristina Bergamaschi^*, Rashmi Jalah, Viraj Kulkarni, Margherita Rosati^*, Gen-Mu Zhang^*,, Candido Alicea, Andrei S. Zolotukhin, Barbara K. Felber and George N. Pavlakis^2,*

^* Human Retrovirus Section and Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702

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-15R. Coinjection of SSP IL-15- and IL-15R-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-15R in the same cell. The apparent t_1/2 of this heterodimer is lower compared with LSP IL-15/IL-15R, due to different intracellular processing. Coexpression of both LSP IL-15 and SSP IL-15 in the presence of IL-15R results in lower levels of bioactive IL-15, indicating that LSP and SSP IL-15 compete for the binding to IL-15R when expressed in the same cell. Because the SSP IL-15 interaction to IL-15R 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.

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.

¹ This work was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research.

² Address correspondence and reprint requests to Dr. George N. Pavlakis, Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201. E-mail address: pavlakig{at}mail.nih.gov

³ Abbreviations used in this paper: LSP, long signal peptide; HA, hemagglutinin; SSP, short signal peptide; BGH, bovine growth hormone.