Tethering transcription factors outside the nucleus is a well-established mechanism for regulating their activity. This typically involves membrane-bound organelles or the plasma membrane. In case of the Hedgehog signaling pathway, surprisingly it is the microtubule cytoskeleton that is involved in cytoplasmic tethering of the transcription factor Gli (Glioma Associated Oncogene).  In this work, we uncovered a unique DNA-mimicry based mechanism by which Gli is tethered to the microtubules at the distal tip of the primary cilia. The coiled-coil dimerization domain of the ciliary kinesin, Kif7 mimics the size, shape and surface charge of DNA to interact with the canonical DNA-binding zinc-finger domain of Gli and recruit it to microtubules. We found that Gli is not a passive cargo, and it increases the kinesin-microtubule affinity, and regulates the recruitment of both Kif7 and Gli at the distal cilia tips upon Hedgehog pathway activation. We exploited this coiled-coil-based Kif7-Gli interaction to inhibit the nuclear localization of Gli, a strategy that can potentially be used to downregulate erroneously activated Gli in human cancers.

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