The Caenorhabditis elegans Elongator complex regulates neuronal alpha-tubulin acetylation.
The Caenorhabditis elegans Elongator complex regulates neuronal alpha-tubulin acetylation.
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DOI：
10.1371/journal.pgen.1000820
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发表时间：
2010-01-22
期刊：
影响因子：
4.5
通讯作者：
Cassata G
中科院分区：
文献类型：
--
作者：
Solinger JA;Paolinelli R;Klöss H;Scorza FB;Marchesi S;Sauder U;Mitsushima D;Capuani F;Stürzenbaum SR;Cassata G
虽然已知乙酰化的α-微管蛋白是神经元中稳定微管的标志物，但迄今为止，调节α-微管蛋白乙酰化的精确因子在很大程度上是未知的。因此，在线虫秀丽隐杆线虫中进行了遗传筛选，鉴定了延伸体复合物作为α-微管蛋白乙酰化的可能调节剂。突变动物的详细表征表明，乙酰转移酶活性的延长确实需要正确的乙酰化微管和神经元的发展。此外，微管上囊泡的速度受到Elongator突变的影响。延长子突变体也表现出神经递质水平的缺陷。此外，α-微管蛋白的乙酰化被证明是一种新的信号，通过调节α-微管蛋白的更新，从而影响神经元的形状，微调微管动力学。鉴于在伸长子的乙酰转移酶亚基（Elp 3）和支架亚基（Elp 1）中的突变先前已与人类神经退行性疾病（即肌萎缩侧索硬化症和家族性自主神经功能障碍）相关联，分别突出了这项工作的重要性，并为理解其病因提供了新的见解。我们能够证明如何筛选，利用线虫模式生物秀丽隐杆线虫，产生了新的发现，延长蛋白复合物是神经元发育和微管乙酰化的关键。其他科学家先前已经表明，延长子对转录很重要，但也假设细胞质中存在一种迄今为止未知的功能。微管乙酰化的调节对细胞功能确实很重要。我们的研究结果提供了第一个诱人的见解蠕虫显示神经元表型，可能与微管乙酰化程度的变化。我们还指出，Elongator本身具有明确的乙酰转移酶功能，很可能直接负责α-微管蛋白的乙酰化。总之，我们讨论了如何调控微管乙酰化可能会影响对人类神经退行性疾病，即家族性自主神经功能障碍和肌萎缩侧索硬化症的理解。
Although acetylated α-tubulin is known to be a marker of stable microtubules in neurons, precise factors that regulate α-tubulin acetylation are, to date, largely unknown. Therefore, a genetic screen was employed in the nematode Caenorhabditis elegans that identified the Elongator complex as a possible regulator of α-tubulin acetylation. Detailed characterization of mutant animals revealed that the acetyltransferase activity of the Elongator is indeed required for correct acetylation of microtubules and for neuronal development. Moreover, the velocity of vesicles on microtubules was affected by mutations in Elongator. Elongator mutants also displayed defects in neurotransmitter levels. Furthermore, acetylation of α-tubulin was shown to act as a novel signal for the fine-tuning of microtubules dynamics by modulating α-tubulin turnover, which in turn affected neuronal shape. Given that mutations in the acetyltransferase subunit of the Elongator (Elp3) and in a scaffold subunit (Elp1) have previously been linked to human neurodegenerative diseases, namely Amyotrophic Lateral Sclerosis and Familial Dysautonomia respectively highlights the importance of this work and offers new insights to understand their etiology. We were able to demonstrate how a screen, that utilized the nematode model organism Caenorhabditis elegans, yielded the novel discovery that the Elongator protein complex is critical for neuronal development and microtubule acetylation. Other scientists have previously shown that the Elongator is important for transcription, but also hypothesized that a hitherto unknown function within the cytoplasm prevails. Regulation of microtubule acetylation is indeed important for cellular function. Our results provide the first tantalizing insights of how worms display neuronal phenotypes that may be linked to changes in degrees of acetylation of microtubules. We also point out that the Elongator itself has a defined acetyltransferase function that could well be directly responsible for the acetylation of α-tubulin. In conclusion, we discuss how the regulation of microtubule acetylation might impact on the understanding of human neurodegenerative diseases, namely Familial Dysautonomia and Amyotrophic Lateral Sclerosis.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
在嗜热四膜虫中，赖氨酸40在α-微管蛋白中的乙酰化并不是必需的。
影响因子：
7.8
作者：
GAERTIG, J;CRUZ, MA;BOWEN, J;GU, L;PENNOCK, DG;GOROVSKY, MA
通讯作者：
GOROVSKY, MA
影响因子：
56.9
作者：
Ding, Mei;Chao, Dan;Shen, Kang
通讯作者：
Shen, Kang
影响因子：
64.5
作者：
Akhmanova, A;Hoogenraad, CC;Galjart, N
通讯作者：
Galjart, N