BACKGROUND: IL-15 can either be transpresented by IL-15Rα or be secreted. RESULTS: New N- and C-terminal splice versions of human IL-15Rα determine whether IL-15 is secreted or stays bound to the cell membrane. CONCLUSION: IL-15Rα isoforms determine the mode of action of IL-15. SIGNIFICANCE: IL-15Rα isoforms may modify immune response outcomes in humans. Species-specific differences of post-translational modifications suggested the existence of human IL-15Rα isoforms. We identified eight new isoforms that are predicted to modify the intracellular C termini of IL-15Rα, and another N-terminal exon "Ex2A" that was consistently present in all but one of the C-terminal isoforms. Ex2A encodes a 49-amino acid domain that allowed the transfer of IL-15/IL-15Rα complex to the cell surface but prevented its cleavage from cell membranes and its secretion thus facilitating the transpresentation of IL-15 as part of the immunological synapse. The Ex2A domain also affected the O-glycosylation of IL-15Rα that explained the species-specific differences. The Ex2A domain appeared to be removed from major IL-15Rα species during protein maturation, but both Ex2A and IL-15Rα appeared on the surface of monocytic cells upon activation. The membrane-associated form of the only C-terminal isoform that lacked Ex2A (IC3) was retained inside the cell, but soluble IL-15/IL-15Rα complexes were readily released from cells that expressed IL-15/IL-15Rα-IC3 thus limiting this IL-15/IL-15Rα isoform to act as a secreted molecule. These data suggest that splice versions of IL-15Rα determine the range of IL-15 activities.
BACKGROUND:IL-15 can either be transpresented by IL-15Rα or be secreted. RESULTS: New N- and C-terminal splice versions of human IL-15Rα determine whether IL-15 is secreted or stays bound to the cell membrane. CONCLUSION: IL-15Rα isoforms determine the mode of action of IL-15. SIGNIFICANCE: IL-15Rα isoforms may modify immune response outcomes in humans. Species-specific differences of post-translational modifications suggested the existence of human IL-15Rα isoforms. We identified eight new isoforms that are predicted to modify the intracellular C termini of IL-15Rα, and another N-terminal exon "Ex2A" that was consistently present in all but one of the C-terminal isoforms. Ex2A encodes a 49-amino acid domain that allowed the transfer of IL-15/IL-15Rα complex to the cell surface but prevented its cleavage from cell membranes and its secretion thus facilitating the transpresentation of IL-15 as part of the immunological synapse. The Ex2A domain also affected the O-glycosylation of IL-15Rα that explained the species-specific differences. The Ex2A domain appeared to be removed from major IL-15Rα species during protein maturation, but both Ex2A and IL-15Rα appeared on the surface of monocytic cells upon activation. The membrane-associated form of the only C-terminal isoform that lacked Ex2A (IC3) was retained inside the cell, but soluble IL-15/IL-15Rα complexes were readily released from cells that expressed IL-15/IL-15Rα-IC3 thus limiting this IL-15/IL-15Rα isoform to act as a secreted molecule. These data suggest that splice versions of IL-15Rα determine the range of IL-15 activities.
Authors: Patrick R Burkett; Rima Koka; Marcia Chien; Sophia Chai; Faye Chan; Averil Ma; David L Boone Journal: Proc Natl Acad Sci U S A Date: 2003-04-01 Impact factor: 11.205
Authors: M K Kennedy; M Glaccum; S N Brown; E A Butz; J L Viney; M Embers; N Matsuki; K Charrier; L Sedger; C R Willis; K Brasel; P J Morrissey; K Stocking; J C Schuh; S Joyce; J J Peschon Journal: J Exp Med Date: 2000-03-06 Impact factor: 14.307