Analyzing the molecular roles of the Gumby/Fam105b/Otulin linear deubiquitinase and its relative Fam105a in development

真核细胞使用一种叫做“泛素”的小标签作为“邮编”，将蛋白质送到正确的位置。泛素本身可以添加其他泛素分子，以构建泛素“链”。这些链条充当了更精确的“邮政编码”。虽然所有真核生物都有泛素链，但只有脊椎动物（脊索动物）才有最近发现的“线性泛素”链。在患有神经退行性疾病（如ALS或帕金森氏症）的患者的大脑中可以看到泛素标签团块，这一鲜为人知的观察结果强调了泛素标签及其移除的重要性。***通过小鼠遗传学、结构和蛋白质组学分析，我们发现了Gumby/Otulin/Fam105b基因，该基因可以选择性地从蛋白质中去除线性泛素链。我们发现线性泛素化的蛋白质是必要的适当的神经元和面部发育和血管的形成。（我们将这只突变小鼠命名为“gumby”，因为胚胎与粘土角色gumby有共同的特征：由于血管形成不当，它们看起来是绿色的，由于颅面异常而具有“微笑”，并且头部呈方形。）缺乏Gumby基因的小鼠胚胎在妊娠中期死亡。我们还发现Gumby调节Wnt/无翼信号通路，该通路在发育和疾病中起重要作用。Gumby只有一个密切相关的基因——Fam105a基因。Fam105a只存在于陆生动物和哺乳动物中。通过产生缺乏Fam105a的小鼠突变，我们发现Fam105a在最近进化出现的高度适应性器官和组织中发挥重要作用。在这里，我们通过分析小鼠突变体和鉴定Fam105a的伴侣蛋白，重点了解Fam105a的这些作用和调控的信号通路。***由于Gumby和Fam105a都是在最近的进化过程中出现的，了解它们的基本功能和可能交叉的分子途径与理解哺乳动物和人类生物学特别相关，并且可以在小鼠中进行最好的研究。最后，可以很容易地设计出OTU家族去泛素酶的抑制剂和激活剂，例如Gumby和Fam105a，因此，Gumby和Fam105a可能在未来为调节特定的生物途径提供有用的靶点

Eukaryotic cells use a small tag called "ubiquitin" as a " zipcode" to send proteins to the right location. Ubiquitin itself can have other ubiquitin molecules added to it to build ubiquitin "chains". These chains serve as more precise "zipcodes". While all eukaryotes build ubiquitin chains, only animals with backbones (chordates) build the more recently discovered "linear ubiquitin" chain. The importance of ubiquitin tags - and their removal - is underscored by the poorly understood observation that clumps of ubiquitin tags are seen in brains of patients suffering from neurodegenerative diseases, such as ALS or Parkinson's.***  By using mouse genetics, structural and proteomic analyses, we discovered the Gumby/Otulin/Fam105b gene, which can selectively remove linear ubiquitin chains from proteins. We found that linear ubiquitination of proteins is essential for proper neuronal and facial development and formation of blood vessels. (We named the mouse mutant "gumby" because the embryos shared features with the claymation character Gumby: they look greenish due to improper blood vessel formation, have a "smile" because of craniofacial anomalies and a squarish head.) Mouse embryos that lack the Gumby gene die in midgestation. We also found that Gumby regulates the Wnt/wingless signaling pathway, which plays essential roles in development and disease.***  Gumby has only one closely related gene- the Fam105a gene. Fam105a is only found in terrestrial animals and mammals. By generating a mouse mutation lacking Fam105a, we found that Fam105a plays essential roles in highly adapted organs and tissues that emerged more recently evolutionarily. Here we are focusing on understanding these roles and the signaling pathways that Fam105a regulates by analyzing the mouse mutant and identifying the partner proteins of Fam105a.***  As both Gumby and Fam105a have emerged evolutionarily relatively recently, understanding their essential functions and possibly intersecting molecular pathways is particularly relevant to understanding mammalian and human biology and can be best studied in the mouse. Finally, both inhibitors and activators for deubiquitinases of the OTU family, such as Gumby and Fam105a, can be readily designed and, thus, Gumby and Fam105a may in the future provide useful targets for modulating specific biological pathways.**