Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants.
Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants.
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与秀丽隐杆线虫延伸器突变体的神经和发育功能障碍相关的tRNA修饰缺陷。
DOI：
10.1371/journal.pgen.1000561
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发表时间：
2009-07
期刊：
影响因子：
4.5
通讯作者：
Byström AS
中科院分区：
文献类型：
--
作者：
Chen C;Tuck S;Byström AS
延伸复合物（Elongator）是一种由六个亚基组成的蛋白质复合物，从酵母到人类都具有保守性。人类延伸复合物同源物hELP1的突变与神经系统疾病家族性自主神经功能异常有关。然而，延伸复合物在多细胞动物中的功能以及人类的突变如何影响神经功能尚未完全了解。在此我们表明，在秀丽隐杆线虫中，延伸复合物的组成成分ELPC - 1和ELPC - 3是tRNA中摆动尿苷的5 - 氨甲酰甲基和5 - 甲基羧甲基侧链形成所必需的。缺乏这些修饰会导致秀丽隐杆线虫的翻译缺陷。ELPC - 1::GFP和ELPC - 3::GFP报告基因在盐趋化性学习所需的一部分化学感觉神经元中强烈表达。elpc - 1或elpc - 3基因失活会导致这一过程出现缺陷，与神经肽的转录后减少以及突触间隙中乙酰胆碱积累减少有关。elpc - 1和elpc - 3突变与tuc - 1突变一起具有合成致死性，tuc - 1是具有5′甲基羧甲基侧链的tRNA硫醇化所必需的。elpc - 1;tuc - 1和elpc - 3;tuc - 1双突变体表现出发育缺陷。我们的研究结果表明，通过对tRNA修饰的影响，延伸复合物促进神经功能和发育。
蛋白质合成的效率可通过翻译机制的各种成分的改变来调节。在翻译过程中，转运RNA作为衔接分子将mRNA解码为蛋白质，因此在基因表达中起着核心作用。在tRNA成熟过程中，一部分正常核苷会发生修饰。tRNA反密码子区域的修饰核苷对高效翻译很重要。我们发现，在秀丽隐杆线虫中，延伸复合物的组成成分是反密码子区域中一组特定tRNA修饰形成所必需的。我们观察到延伸复合物突变的线虫中翻译效率降低以及神经递质产生减少。延伸复合物在真核生物中是保守的，人类延伸复合物的一个亚基的突变会导致一种严重的神经退行性疾病——家族性自主神经功能异常（FD）。在人类中，延伸复合物是否通过tRNA修饰在翻译水平上作用以调节神经元过程尚不清楚。我们在秀丽隐杆线虫中的观察结果，以及酵母延伸复合物在翻译中的作用，表明延伸复合物在tRNA修饰方面的功能是保守的。延伸复合物失活可能通过影响翻译导致神经元缺陷。
Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5′methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development. The efficiency of protein synthesis can be modulated by alterations of various components of the translation machinery. In translation, transfer RNAs act as adapter molecules that decode mRNA into protein and thereby play a central role in gene expression. In the tRNA maturation process, a subset of the normal nucleosides undergoes modifications. Modified nucleosides in the tRNA anticodon region are important for efficient translation. We found that, in the worm C. elegans, components of the Elongator complex are required for the formation of a certain set of tRNA modifications in the anticodon region. We observed a reduced efficiency of translation as well as a lower production of neurotransmitters in Elongator mutant worms. Elongator is conserved in eukaryotes, and mutations in a subunit of human Elongator cause a severe neurodegenerative disease, familial dysautonomia (FD). It is unclear in humans whether Elongator acts on the translational level through tRNA modification to regulate neuronal processes. Our observations in C. elegans, together with the role of yeast Elongator in translation, show that the function of Elongator in tRNA modification is conserved. Inactivation of Elongator may cause neuronal defects by affecting translation.
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