Hedgehog 'off' state

Hedgehog is a secreted morphogen that has evolutionarily conserved roles in body organization by regulating the activity of the Ci/Gli transcription factor family. In Drosophila in the absence of Hh signaling, full-length Ci is partially degraded by the proteasome to generate a truncated repressor form that translocates to the nucleus to represses Hh-responsive genes. Binding of Hh ligand to the Patched (PTC) receptor allows the 7-pass transmembrane protein Smoothened (SMO) to be activated in an unknown manner, disrupting the partial proteolysis of Ci and allowing the full length activator form to accumulate (reviewed in Ingham et al, 2011; Briscoe and Therond, 2013). <br>While many of the core components of Hh signaling are conserved from flies to humans, the pathways do show points of significant divergence. Notably, the human genome encodes three Ci homologues, GLI1, 2 and 3 that each play slightly different roles in regulating Hh responsive genes. GLI3 is the primary repressor of Hh signaling in vertebrates, and is converted to the truncated GLI3R repressor form in the absence of Hh. GLI2 is a potent activator of transcription in the presence of Hh but contributes only minimally to the repression function. While a minor fraction of GLI2 protein is processed into the repressor form in the absence of Hh, the majority is either fully degraded by the proteasome or sequestered in the full-length form in the cytosol by protein-protein interactions. GLI1 lacks the repression domain and appears to be an obligate transcriptional activator (reviewed in Briscoe and Therond, 2013).<br> Vertebrate but not fly Hh signaling also depends on the movement of pathway components through the primary cilium. The primary cilium is a non-motile microtubule based structure whose construction and maintenance depends on intraflagellar transport (IFT). Anterograde IFT moves molecules from the ciliary base along the axoneme to the ciliary tip in a manner that requires the microtubule-plus-end directed kinesin KIF3 motor complex and the IFT-B protein complex, while retrograde IFT back to the ciliary base depends on the minus-end directed dynein motor and the IFT-A complex. Genetic screens have identified a number of cilia-related proteins that are required both to maintain Hh in the 'off' state and to transduce the signal when the pathway is activated (reviewed in Hui and Angers, 2011; Goetz and Anderson, 2010).

刺猬素是一种分泌性形态发生素，其在生物体组织中的进化保守作用通过调节Ci/Gli转录因子家族的活性得以实现。在果蝇中，当缺乏Hh信号传导时，Ci的全长蛋白在蛋白酶体作用下部分降解，从而生成截短形式的阻遏蛋白，该蛋白转移至细胞核以抑制Hh响应基因的表达。Hh配体与Patched（PTC）受体的结合以未知的方式激活了七次跨膜蛋白Smoothened（SMO），破坏了Ci的部分蛋白水解，并允许全长激活形式积累（详见Ingham等人，2011年；Briscoe和Therond，2013年）。尽管从果蝇到人类，Hh信号传导的核心成分得到了保守，但通路确实存在显著的分化点。值得注意的是，人类基因组编码了三种Ci同源基因GLI1、2和3，它们在调节Hh响应基因方面发挥着略微不同的作用。GLI3是脊椎动物Hh信号传导的主要阻遏因子，在缺乏Hh的情况下转化为截短形式的GLI3R阻遏蛋白。GLI2在Hh存在的情况下是一种强大的转录激活因子，但对阻遏功能的贡献微乎其微。在缺乏Hh的情况下，虽然GLI2蛋白的一小部分被加工成阻遏形式，但大部分要么被蛋白酶体完全降解，要么通过蛋白质-蛋白质相互作用在细胞质中以全长形式隔离。GLI1缺乏阻遏结构域，似乎是一种必需的转录激活因子（详见Briscoe和Therond，2013年）。此外，与果蝇不同，脊椎动物的Hh信号传导还依赖于通路成分通过初级纤毛的移动。初级纤毛是一种非移动的微管基结构，其构建和维护依赖于纤毛内运输（IFT）。顺行IFT将分子从纤毛基沿轴突微管移动到纤毛尖端，这一过程需要微管正端导向的驱动蛋白KIF3运动复合物和IFT-B蛋白复合物，而逆行IFT返回纤毛基则依赖于负端导向的动粒蛋白和IFT-A复合物。遗传筛选已经鉴定出许多与纤毛相关的蛋白质，这些蛋白质对于维持Hh处于“关闭”状态以及在通路被激活时传递信号是必需的（详见Hui和Angers，2011年；Goetz和Anderson，2010年）。