Chen Miao-Hsueh, Wilson Christopher W, Li Ya-Jun, Law Kelvin King Lo, Lu Chi-Sheng, Gacayan Rhodora, Zhang Xiaoyun, Hui Chi-chung, Chuang Pao-Tien
Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94158, USA.
Genes Dev. 2009 Aug 15;23(16):1910-28. doi: 10.1101/gad.1794109.
A central question in Hedgehog (Hh) signaling is how evolutionarily conserved components of the pathway might use the primary cilium in mammals but not fly. We focus on Suppressor of fused (Sufu), a major Hh regulator in mammals, and reveal that Sufu controls protein levels of full-length Gli transcription factors, thus affecting the production of Gli activators and repressors essential for graded Hh responses. Surprisingly, despite ciliary localization of most Hh pathway components, regulation of Gli protein levels by Sufu is cilium-independent. We propose that Sufu-dependent processes in Hh signaling are evolutionarily conserved. Consistent with this, Sufu regulates Gli protein levels by antagonizing the activity of Spop, a conserved Gli-degrading factor. Furthermore, addition of zebrafish or fly Sufu restores Gli protein function in Sufu-deficient mammalian cells. In contrast, fly Smo is unable to translocate to the primary cilium and activate the mammalian Hh pathway. We also uncover a novel positive role of Sufu in regulating Hh signaling, resulting from its control of both Gli activator and repressor function. Taken together, these studies delineate important aspects of cilium-dependent and cilium-independent Hh signal transduction and provide significant mechanistic insight into Hh signaling in diverse species.
刺猬信号通路（Hh）中的一个核心问题是，该通路中在进化上保守的组分如何在哺乳动物中利用初级纤毛，而在果蝇中却并非如此。我们聚焦于哺乳动物中主要的Hh调节因子融合抑制因子（Sufu），发现Sufu控制全长Gli转录因子的蛋白质水平，从而影响对Hh梯度反应至关重要的Gli激活因子和抑制因子的产生。令人惊讶的是，尽管大多数Hh信号通路组分都定位于纤毛，但Sufu对Gli蛋白质水平的调节却不依赖于纤毛。我们提出，Hh信号通路中依赖Sufu的过程在进化上是保守的。与此一致的是，Sufu通过拮抗保守的Gli降解因子Spop的活性来调节Gli蛋白质水平。此外，添加斑马鱼或果蝇的Sufu可恢复Sufu缺陷型哺乳动物细胞中的Gli蛋白质功能。相比之下，果蝇的Smo无法转运至初级纤毛并激活哺乳动物的Hh信号通路。我们还发现了Sufu在调节Hh信号通路中的一种新的正向作用，这源于它对Gli激活因子和抑制因子功能的控制。综上所述，这些研究阐明了依赖纤毛和不依赖纤毛的Hh信号转导的重要方面，并为不同物种中Hh信号通路提供了重要的机制性见解。
