Natural splicing of exon 2 of human interleukin-15 receptor α-chain mRNA results in a shortened form with a distinct pattern of expression

We report the existence of eight different interleukin-15 receptor alpha-chain (IL-15R alpha) transcripts resulting from exon-splicing mechanisms within the IL-15R alpha gene. Two main classes of transcripts can be distinguished that do or do not (Delta 2 isoforms) contain the exon 2-coding sequence. Both classes were expressed in numerous cell lines and tissues (including peripheral blood lymphocytes) art comparable levels and could be transcribed in COS-7 cells, and the proteins were expressed at the cell surface. Both receptor forms displayed numerous glycosylation stales, reflecting differential usage of a single N-glycosylation site as well as extensive O-glycosylations. Whereas IL-15R alpha bound IL-15 with high affinity, Delta 2IL-15R alpha was unable to bind IL-15, thus revealing the indispensable role of the exon 2-encoded domain in cytokine binding. A large proportion of IL-15R alpha was expressed at the nuclear membrane with some intranuclear localization, supporting a potential direct action of the IL-15 IL-15R alpha complex at the nuclear level. In sharp contrast, Delta 2IL-15R alpha was found only in the non-nuclear membrane compartments, indicating that the exon alpha-encoded domain (which is shown to contain a potential nuclear localization signal) plays an important role in receptor post-translational routing. Together, our data indicate that exon 2 splicing of human IL-15R alpha is a natural process that might play regulatory roles at different levels.