Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Fred and Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Cell Mol Life Sci. 2022 Apr 29;79(5):266. doi: 10.1007/s00018-022-04233-1.
Hedgehog (Hh) signaling is evolutionarily conserved and plays an instructional role in embryonic morphogenesis, organogenesis in various animals, and the central nervous system organization. Multiple feedback mechanisms dynamically regulate this pathway in a spatiotemporal and context-dependent manner to confer differential patterns in cell fate determination. Hh signaling is complex due to canonical and non-canonical mechanisms coordinating cell-cell communication. In addition, studies have demonstrated a regulatory framework of Hh signaling and shown that cholesterol is vital for Hh ligand biogenesis, signal generation, and transduction from the cell surface to intracellular space. Studies have shown the importance of a specific cholesterol pool, termed accessible cholesterol, which serves as a second messenger, conveying signals between smoothened (Smo) and patched 1 (Ptch1) across the plasma and ciliary membranes. Remarkably, recent high-resolution structural and molecular studies shed new light on the interplay between Hh signaling and cholesterol in membrane biology. These studies elucidated novel mechanistic insight into the release and dispersal of cholesterol-anchored Hh and the basis of Hh recognition by Ptch1. Additionally, the putative model of Smo activation by cholesterol binding and/or modification and Ptch1 antagonization of Smo has been explicated. However, the coupling mechanism of Hh signaling and cholesterol offered a new regulatory principle in cell biology: how effector molecules of the Hh signal network react to and remodel cholesterol accessibility in the membrane and selectively activate Hh signaling proteins thereof. Recognizing the biological importance of cholesterol in Hh signaling activation and transduction opens the door for translational research to develop novel therapeutic strategies. This review looks in-depth at canonical and non-canonical Hh signaling and the distinct proposed model of cholesterol-mediated regulation of Hh signaling components, facilitating a more sophisticated understanding of the Hh signal network and cholesterol biology.
Hedgehog (Hh) 信号在进化上是保守的，在胚胎形态发生、各种动物的器官发生以及中枢神经系统组织中发挥指导作用。多种反馈机制以时空和上下文依赖的方式动态调节该途径，赋予细胞命运决定的不同模式。Hh 信号由于规范和非规范机制协调细胞间通讯而变得复杂。此外，研究已经证明了 Hh 信号的调节框架，并表明胆固醇对于 Hh 配体的生物发生、信号产生以及从细胞膜表面到细胞内空间的转导是至关重要的。研究表明，一种特定的胆固醇池，称为可及胆固醇，作为第二信使，在 smoothened (Smo) 和 patched 1 (Ptch1) 之间传递信号，穿过质膜和纤毛膜，这非常重要。值得注意的是，最近的高分辨率结构和分子研究为膜生物学中 Hh 信号和胆固醇之间的相互作用提供了新的见解。这些研究阐明了胆固醇锚定的 Hh 的释放和分散以及 Ptch1 识别 Hh 的基础的新的机制见解。此外，已经阐明了 Smo 通过胆固醇结合和/或修饰的激活以及 Ptch1 对 Smo 的拮抗的假定模型。然而，Hh 信号和胆固醇的偶联机制提供了细胞生物学中的一个新的调节原则：Hh 信号网络的效应分子如何响应和重塑膜中的胆固醇可及性，并选择性地激活其中的 Hh 信号蛋白。认识到胆固醇在 Hh 信号激活和转导中的生物学重要性为开发新的治疗策略的转化研究开辟了道路。这篇综述深入探讨了规范和非规范的 Hh 信号以及胆固醇介导的 Hh 信号成分调节的独特拟议模型，有助于更深入地理解 Hh 信号网络和胆固醇生物学。
