Dynamic bidirectional transport between the nucleus and the cytoplasm is critical for the regulation of many transcription factors, whose levels inside the nucleus must be tightly controlled. Efficient shuttling across the nuclear membrane is especially crucial with regard to the Hedgehog (Hh) pathway, where the transcriptional signal depends on the fine balance between the amounts of Gli protein activator and repressor forms in the nucleus. The nuclear export machinery prevents the unchecked nuclear accumulation of Gli proteins, but the mechanistic insight into this process is limited. We show that the atypical exportin Xpo7 functions as a major nuclear export receptor that actively excludes Gli2 from the nucleus and controls the outcome of Hh signaling. We show that Xpo7 interacts with several domains of Gli2 and that this interaction is modulated by SuFu, a key negative regulator of Hh signaling. Our data pave the way for a more complete understanding of the nuclear shuttling of Gli proteins and the regulation of their transcriptional activity.

细胞核和细胞质之间的动态双向转运对于许多转录因子的调节至关重要，这些转录因子在细胞核内的水平必须受到严格控制。穿过核膜的有效穿梭对于 Hedgehog (Hh) 途径尤其重要，其中转录信号取决于细胞核中 Gli 蛋白激活剂和阻遏物形式之间的精细平衡。核输出机制可防止 Gli 蛋白不受控制的核积累，但对该过程的机制洞察力是有限的。我们表明，非典型输出蛋白 Xpo7 作为主要的核输出受体发挥作用，主动将 Gli2 从细胞核中排除并控制 Hh 信号传导的结果。我们表明 Xpo7 与 Gli2 的几个域进行交互，并且这种交互受 SuFu 调节，SuFu 是 Hh 信号传导的关键负调节器。我们的数据为更全面地了解 Gli 蛋白的核穿梭及其转录活性的调节铺平了道路。