Secretion and Biological Activity of Short Signal Peptide IL-15 Is Chaperoned by IL-15 Receptor Alpha In Vivo
Secretion and Biological Activity of Short Signal Peptide IL-15 Is Chaperoned by IL-15 Receptor Alpha In Vivo
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DOI：
10.4049/jimmunol.0900693
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发表时间：
2009-09-01
影响因子：
4.4
通讯作者：
Pavlakis, George N.
中科院分区：
文献类型：
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作者：
Bergamaschi, Cristina;Jalah, Rashmi;Pavlakis, George N.
IL-15 的两种已知亚型包含长信号肽 (LSP) 或短信号肽 (SSP)，并由选择性剪接转录物产生。有人提出，SSP IL-15 仅存在于细胞内，其功能尚不清楚。在本研究中，我们表明，与 LSP IL-15 类似，SSP IL-15 在 IL-15R α 共表达时稳定并有效分泌。将 SSP IL-15 和 IL-15R α 表达质粒共注射到小鼠体内，导致生物活性异二聚体 IL-15 的血浆水平增加以及 INK 和 T 细胞的动员和扩增。因此，当在同一细胞中与 IL-15R α 形成异二聚体时，SSP IL-15 会被分泌并具有生物活性。由于细胞内加工不同，与 LSP IL-15/IL-15R α 相比，该异二聚体的表观 t(1/2) 较低。在 IL-15R α 存在的情况下，LSP IL-15 和 SSP IL-15 共表达会导致生物活性 IL-15 水平降低，表明当在同一细胞中表达时，LSP 和 SSP IL-15 竞争与 IL-15R α 的结合。由于 SSP M-15 与 IL-15R α 的相互作用导致复合物的表观稳定性较低，因此 SSP IL-15 充当 LSP IL-15 的竞争性抑制剂。数据表明，选择性剪接的使用是对 IL-15 活性的额外控制水平。 IL-15 的 SSP 和 LSP 形式的表达似乎在许多哺乳动物中都是保守的，这表明 SSP 对于表达具有较低程度或持续时间的生物效应的 IL-15 形式可能很重要。免疫学杂志，2009，183：3064-3072。
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 alpha. Coinjection of SSP IL-15- and IL-15R alpha-expressing plasmids into mice resulted in increased plasma levels of bioactive heterodimeric IL-15 and mobilization and expansion of INK and T cells. Therefore, SSP IL-15 is secreted and bioactive when produced as a heterodimer with IL-15R alpha in the same cell. The apparent t(1/2) of this heterodimer is lower compared with LSP IL-15/IL-15R alpha, due to different intracellular processing. Coexpression of both LSP IL-15 and SSP IL-15 in the presence of IL-15R alpha results in lower levels of bioactive IL-15, indicating that LSP and SSP IL-15 compete for the binding to IL-15R alpha when expressed in the same cell. Because the SSP M-15 interaction to IL-15R alpha 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 Journal of Immunology, 2009, 183: 3064-3072.