Live cell imaging reveals continuous STAT6 nuclear trafficking.
The STAT6 transcription factor is essential for the development of protective immunity; however, the consequences of its activity can also contribute to the pathogenesis of autoimmune disease. Tyrosine phosphorylation is known to activate STAT6 in response to cytokine stimulation, but there is a gap in our understanding of the mechanisms by which it enters the nucleus. In this study, live cell imaging was used in conjunction with photobleaching techniques to demonstrate the continual nuclear import of STAT6, independent of tyrosine phosphorylation. The protein domain required for nuclear entry includes the coiled coil region of STAT6 and functions similarly before or after cytokine stimulation. The dynamic nuclear shuttling of STAT6 seems to be mediated by the classical importin-alpha-importin-beta1 system. Although STAT6 is imported to the nucleus continually, it accumulates in the nucleus following tyrosine phosphorylation as a result of its ability to bind DNA. These findings will impact diagnostic approaches and strategies to block the deleterious effects of STAT6 in autoimmunity.
Chen
Hui-Chen
HC
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
Reich
Nancy C
NC
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D038761:Photobleaching; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014443:Tyrosine