The Hedgehog (Hh) pathway plays diverse roles in cellular processes by activating the transcription factor Cubitus interruptus (Ci). Abnormal regulation of this pathway has been linked to various human diseases. While previous studies have focused on how Ci is regulated in the cytoplasm, the control of nuclear Ci remains poorly understood. In this study, we have found that the transcriptional cofactor Taiman (Tai) functions as an inhibitor of the Hh pathway. Tai interferes with the response of Hh signal, rather than Hh secretion. Our epistatic analyses reveal that Tai works in parallel with Ci to reduce its activity, thereby counteracting organ overgrowth and the activation of target genes caused by Ci overexpression. Specifically, Tai interacts with Ci to decrease its binding to target gene promoters. The Hh signal weakens the interaction between Ci and Tai, releasing the inhibition on Ci. Importantly, this regulatory mechanism is conserved from Drosophila to mammalian cells. Moreover, NCOA1-3 are the mammalian ortholog of Drosophila protein Tai, but only NCOA2 plays a similar role in inhibiting the Hh pathway. These findings reveal an additional way to modulate the transcriptional activity of nuclear Ci.

中文翻译：

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Tai/NCOA2 通过直接靶向转录因子 Ci/GLI 来抑制 Hedgehog 通路


Hedgehog （Hh） 通路通过激活转录因子 Cubitus interruptus （Ci） 在细胞过程中发挥多种作用。该途径的异常调节与各种人类疾病有关。虽然以前的研究集中在 Ci 如何在细胞质中调节，但对核 Ci 的控制仍然知之甚少。在这项研究中，我们发现转录辅因子 Taiman （Tai） 作为 Hh 通路的抑制剂发挥作用。Tai 干扰 Hh 信号的反应，而不是 Hh 分泌。我们的上位性分析表明，Tai 与 Ci 平行作用以降低其活性，从而抵消 Ci 过表达引起的器官过度生长和靶基因激活。具体来说，Tai 与 Ci 相互作用以减少其与靶基因启动子的结合。Hh 信号减弱了 Ci 和 Tai 之间的相互作用，从而释放了对 Ci 的抑制。重要的是，这种调节机制从果蝇到哺乳动物细胞都是保守的。此外，NCOA1-3 是果蝇蛋白 Tai 的哺乳动物直系同源物，但只有 NCOA2 在抑制 Hh 通路方面起类似作用。这些发现揭示了另一种调节核 Ci 转录活性的方法。