Nucleocytoplasmic Transport of the Transcription Factor STAT6

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Chen, Hui-Chen
The Graduate School, Stony Brook University: Stony Brook, NY.
Signal Transducer and Activator of Transcription 6 (STAT6) is a member of the STAT family of transcription factors that regulate cytokine signaling pathways. STATs are activated by tyrosine phosphorylation by receptor-associated Janus kinases (JAKs) and gain the ability to bind DNA. In this manner they transmit signals from the cell membrane to the nucleus to induce expression of genes involved in many biological functions. STAT6 needs to enter the nucleus for its function as a transcription factor. Therefore, regulation of STAT6 nuclear trafficking provides a mechanism to control specific gene expression. STAT6 is primarily activated by interleukin-4 (IL-4) and interleukin-13 (IL-13) and plays an important role in protective immunity including development of T helper 2 (TH2) lymphocytes and normal B cell functions. To assess the dynamic movement of STAT6, I used live cell imaging with photobleaching techniques. This approach has provided critical insight to the spatial distribution of STAT6. I provide evidence that STAT6 is imported continually into the nucleus and independent of tyrosine phosphorylation. In vitro binding assays and importin-β1 siRNA knock down assays indicate that STAT6 uses the importin-α-importin-β1 system for nuclear import. In addition, a region required for nuclear localization was found to map within the coiled-coil domain and is critical for nuclear import and transcriptional function of STAT6. STAT6 is also continuously exported out of the nucleus in a tyrosine phosphorylation-independent manner. Although nuclear import rates of STAT6 are similar before and after tyrosine phosphorylation, nuclear accumulation occurs after tyrosine phosphorylation. I have shown that this is dependent on the DNA-binding ability of STAT6 which results in the decrease of nuclear export rate. Furthermore, the nuclear export process of STAT6 appears to be both Crm1 dependent and independent. These findings will impact diagnostic approaches and strategies to block the deleterious effects of STAT6 in autoimmunity.