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首页> 外文期刊>PLoS Genetics >Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase
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Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase

机译：tambaleante突变小鼠中的进行性浦肯野细胞变性是HERC1 E3泛素连接酶的错义突变的结果。

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The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domains have been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a G?A transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N-terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.
机译：HERC基因家族编码具有两个特征域的蛋白质：HECT和RCC1样。具有HECT结构域的蛋白质已被描述为具有泛素连接酶的功能，而包含RCC1类结构域的蛋白质已被报告具有GTPases调节剂的功能。这两个活动在许多重要的细胞过程（例如细胞周期，细胞信号传导和膜运输）中至关重要。已经发现影响这些结构域的突变与色素性视网膜炎，肌萎缩性侧索硬化和癌症有关。在人类中，已经报道了六个HERC基因，它们编码两个HERC蛋白亚组：大（HERC1-2）和小（HERC3-6）。巨大的HERC1蛋白是第一个被鉴定的蛋白。它通过与网格蛋白，M2-丙酮酸激酶和TSC2蛋白的相互作用参与了膜运输和细胞增殖/生长。已经发现影响HERC家族其他成员的突变与不育和生长迟缓有关。在这里，我们报告了一种称为坦巴兰特的隐性突变的特征，该隐性突变导致进行性浦肯野细胞变性，导致严重的共济失调，导致两个月以上纯合子小鼠的生长和寿命降低。我们将这种突变定位在小鼠9号染色体上，然后进行位置克隆。我们在位置1448处发现了一个GΔA过渡，在HERC1蛋白的高度保守的N端RCC1样结构域中引起了Gly到Glu的取代（Gly483Glu）。用含有正常拷贝的Herc1的小鼠BAC或人的HERC1 cDNA进行的成功转基因抢救证实了我们的发现。组织学和生化研究表明，广泛的自噬与突变蛋白水平的提高和mTOR活性的降低有关。我们关于Herc1基因中第一个突变的观察结果有助于编码E3泛素连接酶的功能注释，并强调了该蛋白在浦肯野细胞生理学中的关键和意想不到的作用。

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