Abstract：
Wnts are lipid-modified signaling glycoproteins present in all metazoans that play key roles in development and homeostasis. Post-translational modifications of Wnts regulate their function. Wnts have a unique post-translational modification, O-linked palmitoleation, that is absolutely required for their function. This Wnt-specific modification occurs during Wnt biosynthesis in the endoplasmic reticulum (ER), catalyzed by the O-acyltransferase Porcupine (PORCN). Palmitoleation is required for Wnt to bind to its transporter Wntless (WLS/Evi) as well as to its receptor Frizzled (FZD). Recent structural studies have illustrated how PORCN recognizes its substrates, and how drugs inhibit this. The abundance of WLS is tightly regulated by intracellular recycling and ubiquitylation-mediated degradation in the ER. The function of Wnt glycosylation is less well understood, and the sites and types of glycosylation are not largely conserved among different Wnts. In polarized tissues, the type of glycans can determine whether the route of trafficking is apical or basolateral. In addition, pairing of the 24 highly conserved cysteines in Wnts to form disulfide bonds is critical in maintaining proper structure and activities. Extracellularly, the amino terminus of a subset of Wnts can be cleaved by a dedicated glycosylphosphatidylinositol (GPI)-anchored metalloprotease TIKI, resulting in the inactivation of these Wnt proteins. Additionally, NOTUM is a secreted extracellular carboxylesterase that removes the palmitoleate moiety from Wnt, antagonizing its activity. In summary, Wnt signaling activity is controlled at multiple layers by post-translational modifications.
摘要：
Wnts是存在于所有后生动物中的脂质修饰的信号糖蛋白，在发育和稳态中起关键作用。Wnts的翻译后修饰调节其功能。Wnts具有独特的翻译后修饰，O-连接的棕榈酸,这是他们的功能所必需的。这种Wnt特异性修饰发生在内质网（ER）的Wnt生物合成过程中，由O-酰基转移酶Porcupine（PORCN）催化。Wnt结合其转运蛋白Wnless(WLS/Evi)及其受体Frizzled(FZD)需要棕榈酸。最近的结构研究说明了PORCN如何识别其底物，以及药物如何抑制这种情况。WLS的丰度受到ER中的细胞内再循环和泛素化介导的降解的严格调节。Wnt糖基化的功能不太清楚，糖基化的位点和类型在不同的Wnt中并不基本保守。在极化组织中，聚糖的类型可以确定运输途径是顶端还是基底外侧。此外,将Wnt中的24个高度保守的半胱氨酸配对以形成二硫键对于维持适当的结构和活性是至关重要的。细胞外，Wnts子集的氨基末端可以被专用的糖基磷脂酰肌醇（GPI）锚定的金属蛋白酶TIKI切割，导致这些Wnt蛋白失活。此外,NOTUM是一种分泌的细胞外羧酸酯酶，可从Wnt中去除棕榈油酸部分，对抗其活动。总之,通过翻译后修饰在多个层处控制Wnt信号传导活性。
