THE 5'-UNTRANSLATED-REGION, SIGNAL PEPTIDE, AND THE CODING SEQUENCE OF THE CARBOXYL-TERMINUS OF IL-15 PARTICIPATE IN ITS MULTIFACETED TRANSLATIONAL CONTROL

We previously reported that the AUG-burdened 5' untranslated region (U TR) of IL-15 mRNA impedes its translation. Here we demonstrate that th e nucleotide or protein sequences of the IL-15 signal peptide and carb oxyl terminus also contribute to the poor translation of IL-15 transcr ipts. In particular, the exchange of the IL-15 signal peptide coding s equence with that of IL-2 increased cellular and secreted levels of IL -15 protein 15- to 20-fold in COS cells, while IL-2 transcripts with t he IL-15 signal peptide generated 30- to 50-fold less IL-2 protein tha n wild-type IL-2, Furthermore, the addition of an artificial epitope t ag to the 3' coding sequence of IL-15 increased its protein production 5- to 10-fold. Combining these two IL-15 message modifications, in ad dition to removing the 5' UTR, increased IL-15 synthesis 250-fold comp ared with a wild-type construct with an intact 5' UTR, These data sugg est that IL-15 mRNA, unlike IL-2 mRNA, may exist in translationally in active pools. By storing translationally quiescent IL-15 mRNA, cells m ight respond to intracellular infections or other stimuli by rapidly t ransforming IL-15 message into one that can be efficiently translated.