Paracrine and Transpresentation Functions of IL-15 Are Mediated by Diverse Splice Versions of IL-15Rα in Human Monocytes and Dendritic Cells
Autor: | Thomas A. Waldmann, Jürgen R. Müller, Sigrid Dubois, Michael J. Kruhlak |
---|---|
Rok vydání: | 2012 |
Předmět: |
Gene isoform
RNA Splicing Immunology Amino Acid Motifs Molecular Sequence Data Biology Biochemistry Monocytes Cell Line Immunological synapse Cell membrane Mice Paracrine signalling Interleukin-15 Receptor alpha Subunit Paracrine Communication medicine Animals Humans Protein Isoforms Secretion Molecular Biology Protein maturation Cells Cultured Interleukin-15 Cell Membrane Dendritic Cells Cell Biology Molecular biology Mice Inbred C57BL Protein Transport medicine.anatomical_structure Interleukin 15 Intracellular |
Zdroj: | Journal of Biological Chemistry. 287:40328-40338 |
ISSN: | 0021-9258 |
Popis: | IL-15 can either be transpresented by IL-15Rα or be secreted.New N- and C-terminal splice versions of human IL-15Rα determine whether IL-15 is secreted or stays bound to the cell membrane.IL-15Rα isoforms determine the mode of action of IL-15.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. |
Databáze: | OpenAIRE |
Externí odkaz: |