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

分析 Gumby/Fam105b/Otulin 线性去泛素酶及其相关 Fam105a 在开发中的分子作用

• 批准号: RGPIN-2015-05475
• 负责人: Cordes, Sabine
• 金额: $ 2.48万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613575
• 关键词: Analyzing; molecular; roles; Gumby; Fam105b

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.

真核细胞使用一种名为“泛素”的小标签作为“邮政编码”，将蛋白质送到正确的位置。泛素本身可以加入其他泛素分子来构建泛素“链”。这些链条就像是更精确的“邮政编码”。虽然所有真核生物都建立泛素链，但只有脊椎动物(脊索动物)建立的是最近发现的“线性泛素链”。一个鲜为人知的观察结果突显了泛素标签的重要性--泛素标签在患有神经退行性疾病(如肌萎缩侧索硬化症或帕金森病)的患者的大脑中可见。 通过小鼠遗传学、结构和蛋白质组学分析，我们发现了Gumby/Otlin/Fam105b基因，它可以选择性地从蛋白质中去除线性泛素链。我们发现，蛋白质的线性泛素化对于神经元和面部的正常发育以及血管的形成是必不可少的。(我们将小鼠突变体命名为Gumby，因为这些胚胎与黏土形成的角色Gumby有共同的特征：由于血管形成不当，它们看起来呈绿色，由于头面部畸形，它们有一个“微笑”，还有一个方形的头。)缺乏Gumby基因的小鼠胚胎会在怀孕中期死亡。我们还发现Gumby调控Wnt/无翼信号通路，该通路在发育和疾病中发挥重要作用。 甘比只有一个密切相关的基因--FAM105a基因。FAM105A只在陆地动物和哺乳动物中发现。通过产生一个缺乏Fam105a的小鼠突变，我们发现Fam105a在最近进化出现的高度适应的器官和组织中发挥着至关重要的作用。在这里，我们通过分析小鼠突变和鉴定Fam105a的伙伴蛋白来了解这些作用和Fam105a调节的信号通路。 由于Gumby和Fam105a在进化上都是相对较新的出现，了解它们的基本功能和可能相交的分子途径对于理解哺乳动物和人类生物学特别相关，最好在小鼠身上进行研究。最后，OTU家族脱泛素酶的抑制剂和激活剂，如Gumby和Fam105a，都可以很容易地设计，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。