Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo.
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.
Bergamaschi
Cristina
C
Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.
Jalah
Rashmi
R
Kulkarni
Viraj
V
Rosati
Margherita
M
Zhang
Gen-Mu
GM
Alicea
Candido
C
Zolotukhin
Andrei S
AS
Felber
Barbara K
BK
Pavlakis
George N
GN
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D021382:Protein Sorting Signals; D055550:Protein Stability; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D018832:Molecular Chaperones; D010446:Peptide Fragments; D020033:Protein Isoforms; D021382:Protein Sorting Signals; D012333:RNA, Messenger
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