STAT3 Nuclear Egress Requires Exportin 7 via Engaging Lysine Acetylation

Nucleocytoplasmic shuttling of signaling molecules is crucial for regulating their activity. Regulation of signal transducer and activator of transcription 3 (STAT3) is critical for normal physiology while STAT3 dysregulation underlies many diseases such as cancer. However, the mechanism(s) underlying STAT3 nuclear egress remains unclear. Here, we show that exportin 7 is critical for STAT3 nuclear egress. Lysine acetylation at K685, frequently found in tumors and tumor cell lines, mediates STAT3 engagement with exportin 7. Blocking acetylation through drug administration or mutation of lysine K685 disrupted STAT3’s physical interaction with exportin 7, leading to STAT3 nuclear retention. Inhibition of STAT3 lysine acetylation significantly altered the functional localization of exportin 7 from the cell cytoplasm toward the nucleus which can be reversed by treating tumor with a lysine-acetylated peptide spanning STAT3 K685. Taken together, our results have identified exportin 7 as an essential karyopherin for STAT3 nucleocytoplasmic shuttling.