Interleukin-15 Delivery Service

Science Signaling  22 Jul 2008:
Vol. 1, Issue 29, pp. ec261
DOI: 10.1126/scisignal.129ec261

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-15Rα, is not expressed. By expressing IL-15 with or without its receptor IL-15Rα 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-15Rα. 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-15Rα that lacked a transmembrane domain, the proteins were secreted into the supernatant and did not associate with the cell surface. Monocytes stimulated with interferon-γ (IFN-γ) showed increased transcription of both IL-15 and IL-15Rα and increased secretion of IL-15. Release of IL-15 from the surface of cells cotransfected with IL-15 and IL-15Rα, or from IFN-γ-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-15Rα 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 α. Mol. Cell. Biol. 28, 4851-4861 (2008). [Abstract] [Full Text]