Hedgehog ligand biogenesis

Mammalian genomes encode three Hedgehog ligands, Sonic Hedgehog (SHH), Indian Hedgehog (IHH) and Desert Hedgehog (DHH). These secreted morphogens can remain associated with lipid rafts on the surface of the secreting cell and affect developmental processes in adjacent cells. Alternatively, they can be released by proteolysis or packaging into vesicles or lipoprotein particles and dispersed to act on distant cells. SHH activity is required for organization of the limb bud, notochord and neural plate, IHH regulates bone and cartilage development and is partially redundant with SHH, and DHH contributes to germ cell development in the testis and formation of the peripheral nerve sheath (reviewed in Pan et al, 2013). <br><br>Despite divergent biological roles, all Hh ligands are subject to proteolytic processing and lipid modification during transit to the surface of the secreting cell (reviewed in Gallet, 2011). Precursor Hh undergoes autoproteolytic cleavage mediated by the C-terminal region to yield an amino-terminal peptide Hh-Np (also referred to as Hh-N) (Chen et al, 2011). No other well defined role for the C-terminal region of Hh has been identified, and the secreted Hh-Np is responsible for all Hh signaling activity. Hh-Np is modified with cholesterol and palmitic acid during transit through the secretory system, and both modifications contribute to the activity of the ligand (Porter et al, 1996; Pepinsky et al, 1998; Chamoun et al, 2001). <br><br>At the cell surface, Hh-Np remains associated with the secreting cell membrane by virtue of its lipid modifications, which promote clustering of Hh-Np into lipid rafts (Callejo et al, 2006; Peters et al, 2004). Long range dispersal of Hh-Np depends on the untethering of the ligand from the membrane through a variety of mechanisms. These include release of monomers through the combined activity of the transmembrane protein Dispatched (DISP2) and the secreted protein SCUBE2, assembly into soluble multimers or apolipoprotein particles or release on the surface of exovesicles (Vyas et al, 2008; Tukachinsky et al, 2012; Chen 2004; Zeng et al, 2001; reviewed in Briscoe and Therond, 2013).

哺乳动物基因组编码三种Hedgehog配体，分别为Sonic Hedgehog（SHH）、Indian Hedgehog（IHH）和Desert Hedgehog（DHH）。这些分泌形态发生素可以与分泌细胞表面的脂筏相结合，从而影响邻近细胞中的发育过程。或者，它们可以通过蛋白酶解、包装成囊泡或脂蛋白颗粒来释放，进而作用于远距离的细胞。SHH活性对于肢芽、脊索和中胚层板组织的形成至关重要，IHH调节骨骼和软骨发育，并在一定程度上与SHH功能冗余，而DHH则参与睾丸中生殖细胞的发育和周围神经被膜的生成（详见Pan等，2013年综述）。尽管这些Hh配体在生物学功能上存在差异，但它们在向分泌细胞表面运输的过程中均会经历蛋白酶解处理和脂质修饰（详见Gallet，2011年综述）。Hh前体通过C端区域的自身蛋白酶解切割产生氨基端肽Hh-Np（亦称Hh-N）（Chen等，2011年）。Hh的C端区域尚未发现其他明确的生物学功能，而分泌的Hh-Np负责所有Hh的信号传导活性。Hh-Np在通过分泌系统运输过程中被胆固醇和棕榈酸修饰，这两种修饰均对配体的活性有所贡献（Porter等，1996年；Pepinsky等，1998年；Chamoun等，2001年）。在细胞表面，Hh-Np通过其脂质修饰与分泌细胞膜相结合，这些修饰促进了Hh-Np在脂筏中的聚集（Callejo等，2006年；Peters等，2004年）。Hh-Np的长距离扩散依赖于通过多种机制将配体从膜上解离。这些机制包括通过跨膜蛋白 Dispatched（DISP2）和分泌蛋白 SCUBE2 的联合作用释放单体，组装成可溶性多聚体或脂蛋白颗粒，或释放到外泌体表面（Vyas等，2008年；Tukachinsky等，2012年；Chen，2004年；Zeng等，2001年；详见Briscoe和Therond，2013年综述）。