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Sci. Signal., 22 July 2008
Vol. 1, Issue 29, p. ec261
[DOI: 10.1126/scisignal.129ec261]


Cytokines Interleukin-15 Delivery Service

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Cytokines are secreted immune signaling molecules, and regulating their release is an important mechanism for controlling their activity. The long form of interleukin-15 (IL-15) is a glycosylated protein that is secreted through the classical secretory pathway from endoplasmic reticulum to Golgi to cell surface. However, in some cells the mRNA for IL-15 is present, yet IL-15 is not secreted. In these cells, the receptor that binds IL-15, IL-15R{alpha}, is not expressed. By expressing IL-15 with or without its receptor IL-15R{alpha} or with variants of the receptor that could not bind IL-15 or were not membrane-associated in COS-7 cells, Duitman et al. showed that transit of IL-15 from the endoplasmic reticulum through the Golgi to the surface required IL-15R{alpha}. When the IL-15 binding site was mutated, IL-15 was retained in the cells in a form that was sensitive to the glycanase Endo H, indicating that it did not proceed through the Golgi but had reached the endoplasmic reticulum. When IL-15 was expressed with an IL-15R{alpha} that lacked a transmembrane domain, the proteins were secreted into the supernatant and did not associate with the cell surface. Monocytes stimulated with interferon-{gamma} (IFN-{gamma}) showed increased transcription of both IL-15 and IL-15R{alpha} and increased secretion of IL-15. Release of IL-15 from the surface of cells cotransfected with IL-15 and IL-15R{alpha}, or from IFN-{gamma}-stimulated monocytes, required proteolysis, which was inhibited by general matrix metalloproteinase inhibitor GM6001. Secretion of IL-15 from cells coexpressing the transmembrane-lacking mutant IL-15R{alpha} was unaffected by GM6001. IL-15 acts as a cell surface-associated juxtacrine signal, and this receptor-mediated mechanism of cell surface delivery explains how the cytokine may be presented to adjacent cells.

E. H. Duitman, Z. Orinska, E. Bulanova, R. Paus, S. Bulfone-Paus, How a cytokine is chaperoned through the secretory pathway by complexing with its own receptor: Lessons from interleukin-15 (IL-15)/IL-15 receptor {alpha}. Mol. Cell. Biol. 28, 4851-4861 (2008). [Abstract] [Full Text]

Citation: N. R. Gough, Interleukin-15 Delivery Service. Sci. Signal. 1, ec261 (2008).

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