GENERATION OF SECRETABLE AND NONSECRETABLE INTERLEUKIN-15 ISOFORMS THROUGH ALTERNATE USAGE OF SIGNAL PEPTIDES

Two isoforms of human interleukin 15 (IL-15) exist. One isoform has a shorter putative signal peptide (21 amino acids) and its transcript sh ows a tissue distribution pattern that is distinct from that of the al ternative IL-15 isoform with a 48-aa signal peptide. The 21-aa signal isoform is preferentially expressed in tissues such as testis and thym us, Experiments using different combinations of signal peptides and ma ture proteins (IL-2, IL-15, and green fluorescent protein) showed that the short signal peptide regulates the fate of the mature protein by controlling the intracellular trafficking to nonendoplasmic reticulum sites, whereas the long signal peptide both regulates the rate of prot ein translation and functions as a secretory signal peptide. As a cons equence, the IL-15 associated with the short signal peptide is not sec reted, but rather is stored intracellularly, appearing in the nucleus and cytoplasmic components, Such production of an intracellular lympho kine is not typical of other soluble interleukin systems, suggesting a biological function for IL-15 as an intracellular molecule.