A long-established strategy for transcription regulation is the tethering of transcription factors to cellular membranes. By contrast, the principal effectors of Hedgehog signalling, the GLI transcription factors, are regulated by microtubules in the primary cilium and the cytoplasm. How GLI is tethered to microtubules remains unclear. Here, we uncover DNA mimicry by the ciliary kinesin KIF7 as a mechanism for the recruitment of GLI to microtubules, wherein the coiled-coil dimerization domain of KIF7, characterized by its striking shape, size and charge similarity to DNA, forms a complex with the DNA-binding zinc fingers in GLI, thus revealing a mode of tethering a DNA-binding protein to the cytoskeleton. GLI increases KIF7 microtubule affinity and consequently modulates the localization of both proteins to microtubules and the cilium tip. Thus, the kinesin–microtubule system is not a passive GLI tether but a regulatable platform tuned by the kinesin–transcription factor interaction. We retooled this coiled-coil-based GLI–KIF7 interaction to inhibit the nuclear and cilium localization of GLI. This strategy can potentially be exploited to downregulate erroneously activated GLI in human cancers.

一个长期确立的转录调控策略是将转录因子束缚在细胞膜上。相比之下，Hedgehog 信号的主要效应子 GLI 转录因子受初级纤毛和细胞质中的微管调节。GLI 如何与微管相连仍不清楚。在这里，我们发现纤毛驱动蛋白 KIF7 的 DNA 模拟是将 GLI 募集到微管的一种机制，其中 KIF7 的卷曲螺旋二聚化结构域以其惊人的形状、大小和与 DNA 的电荷相似性为特征，与GLI 中的 DNA 结合锌指，从而揭示了一种将 DNA 结合蛋白拴在细胞骨架上的模式。GLI 增加 KIF7 微管亲和力，从而调节这两种蛋白质在微管和纤毛尖端的定位。因此，驱动蛋白-微管系统不是被动的 GLI 系链，而是受驱动蛋白-转录因子相互作用调节的可调节平台。我们重组了这种基于卷曲线圈的 GLI-KIF7 相互作用，以抑制 GLI 的核和纤毛定位。这种策略可能被用来下调人类癌症中错误激活的 GLI。