Mast cells express novel functional IL-15 receptor alpha isoforms.
Mast cells previously have been reported to be regulated by IL-15 and to express a distinct IL-15R, termed IL-15RX. To further examine IL-15 binding and signaling in mast cells, we have studied the nature of the IL-15R and some of its biological activities in these cells. In this study, we report the existence of three novel isoforms of the IL-15R alpha chain in murine bone marrow-derived mast cells as a result of an alternative exon-splicing mechanism within the IL-15R alpha gene. These correspond to new mRNA transcripts lacking exon 4; exons 3 and 4; or exons 3, 4, and 5 (IL-15R alpha Delta 4, IL-15R alpha Delta 3,4, IL-15R alpha Delta 3,4,5). After transient transfection in COS-7 cells, all IL-15R alpha isoforms associate with the Golgi apparatus, the endoplasmic reticulum, the perinuclear space, and the cell membrane. Analysis of glycosylation pattern demonstrates the usage of a single N-glycosylation site, while no O-glycosylation is observed. Importantly, IL-15 binds with high affinity to, and promotes the survival of, murine BA/F3 cells stably transfected with the IL-15R alpha isoforms. Furthermore, we report that signaling mediated by IL-15 binding to the newly identified IL-15R alpha isoforms involves the phosphorylation of STAT3, STAT5, STAT6, Janus kinase 2, and Syk kinase. Taken together, our data indicate that murine mast cells express novel, fully functional IL-15R alpha isoforms, which can explain the selective regulatory effects of IL-15 on these cells.
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany.
Elena
E
Bulanova
Vadim
V
Budagian
Zane
Z
Orinska
Hans
H
Krause
Ralf
R
Paus
Silvia
S
Bulfone-Paus
D017398:Alternative Splicing / Q000276:immunology; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology; D007376:Interleukin-2 / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013347:Subcellular Fractions / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; C508024:IL15RA protein, human; C508020:IL2RB protein, human; C508025:Il15ra protein, mouse; C508022:Il2rb protein, mouse; C508023:Il2rb protein, rat; D019409:Interleukin-15; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat