IL-4 induces the proteolytic processing of mast cell STAT6.
IL-4 is a potent, pleiotropic cytokine that, in general, directs cellular activation, differentiation, and rescue from apoptosis. However, in mast cells, IL-4 induces the down-regulation of activation receptors and promotes cell death. Mast cells have been shown to transduce IL-4 signals through a unique C-terminally truncated isoform of STAT6. In this study, we examine the mechanism through which STAT6 is processed to generate this isoform. We demonstrate that STAT6 processing in mast cells is initiated by IL-4-induced phosphorylation and nuclear translocation of full-length STAT6 and subsequent cleavage by a nuclear serine-family protease. The location of the protease in the nucleus ensures that the truncated STAT6 has preferential access to bind DNA. IL-4-responsive target genes in mast cells are identified by chromatin immunoprecipitation of STAT6, including the IL-4 gene itself. These results suggest a molecular explanation for the suppressive effects of IL-4 on STAT6-regulated genes in mast cells.
Sherman
Melanie A
MA
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
Powell
Doris R
DR
Brown
Melissa A
MA
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D050800:STAT6 Transcription Factor; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D020033:Protein Isoforms; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D014443:Tyrosine; D012697:Serine Endopeptidases