Natural Splicing of Exon 2 of Human Interleukin-15 Receptor α-Chain mRNA Results in a Shortened Form with a Distinct Pattern of Expression

Abstract

We report the existence of eight different interleukin-15 receptor ␣-chain (IL-15R␣) transcripts resulting from exon-splicing mechanisms within the IL-15R␣ gene. Two main classes of transcripts can be distinguished that do or do not (⌬2 isoforms) contain the exon 2-coding sequence. Both classes were expressed in numerous cell lines and tissues (including peripheral blood lymphocytes) at 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 states, reflecting differential usage of a single N-glycosylation site as well as extensive O-glycosylations. Whereas IL-15R␣ bound IL-15 with high affinity, ⌬2IL-15R␣ 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␣ was expressed at the nuclear membrane with some intranuclear localization, supporting a potential direct action of the IL-15⅐IL-15R␣ complex at the nuclear level. In sharp contrast, ⌬2IL-15R␣ was found only in the non-nuclear membrane compartments, indicating that the exon 2-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␣ is a natural process that might play regulatory roles at different levels.

Mast Cells Express Novel Functional IL-15 Receptor α Isoforms

“…Furthermore, in addition to an association of IL-15R␣ isoforms with the plasma membrane (Fig. 3B), characteristic ring-like structures, as previously reported by Dubois et al (39), could be detected in the perinuclear area (Fig. 3A).…”

“…Recently, the existence of a novel type of IL-15R␣ mRNA lacking exon 2 and a putative nuclear localization signal has been shown in human tissues (39). The new alternatively spliced products of IL-15R␣ gene from mouse mast cells can be added to the ones already described in human system (39,41). However, we cannot exclude that murine mast cells may also express, although presumably at rather low levels, messages for other IL-15R␣ isoforms than the ones identified in this work.…”

Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Express Functional IL-15 Receptor Complex: Endogenous IL-15 in Autocrine Fashion Enhances Cell Proliferation and Expression of Bcl-xL and Bcl-2

“…Eight splicing variants of the human IL-15R␣ have been identified (44). These include all combinations of exon 2 deletion, exon 3 deletion, and alternative use of exon 7 or 7Ј.…”

“…These include all combinations of exon 2 deletion, exon 3 deletion, and alternative use of exon 7 or 7Ј. Because all, except exon 2 deletion isoforms bind IL-15 with very high affinity (13,44), we have chosen PCR primers located in exon 2 (sense) and exon 5 (antisense). Using these primers, amplification of mRNA encoding all IL-15R␣ variants that contain exon 2, and thus, bind IL-15, can be detected.…”

Celiac Disease: a model autoimmune disease with gene therapy applications

“…Different forms of the IL-15 receptor have been generated 68,69 and in this case it would be required to produce a soluble a-chain receptor that retains the high-affinity binding to IL-15, but lacks the ability to integrate with the beta and gamma chains of the IL-2 receptor in order to neutralize IL-15 but avoid to deliver biologically active IL-15 to cells from which we want to remove it. Indeed, it has recently been described that 'sharing' of IL-15 a-chain receptor might allow cells that are not normally responsive to IL-15 to respond to this cytokine.…”