Human diseases linked to cytoplasmic aminoacyl-tRNA synthetases
Human diseases linked to cytoplasmic aminoacyl-tRNA synthetases
复制标题
DOI：
10.1016/bs.enz.2020.06.009
复制
发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Yang, Xiang-Lei
中科院分区：
文献类型：
--
作者：
Jiang, Lei;Jones, Julia;Yang, Xiang-Lei
作为翻译机器的重要组成部分，氨酰-tRNA 合成酶 (aaRS) 对于细胞活力是不可或缺的。在复杂的多细胞生物体中，aaRS 的这一基本重要性因其广泛的调节功能而进一步扩展，并通过其广泛的人类疾病联系得到体现。本章重点讨论支持细胞质中蛋白质合成的 aaRS 组与疾病的联系，包括也用于线粒体翻译的 GlyRS 和 LysRS。迄今为止，三种主要疾病类型已与细胞质 aaRS 直接相关：首先，自身免疫性抗合成酶综合征 (ASS)，其特征是存在针对八种不同 aaRS 之一的自身抗体；第二，一种周围神经病，即腓骨肌萎缩症 (CMT)，由六种不同 aaRS 的显性单等位基因突变引起；第三，严重的多器官疾病，通常伴有发育迟缓，由几乎所有细胞质 aaRS 的隐性双等位基因突变引起。本章将广泛涵盖这些类型中的每一种，较少关注 CMT。复杂生物体中细胞质 aaRS 的一个有趣特征是形成多合成酶复合物 (MSC)，其中包含 9 个 aaRS 和 3 个非酶支架蛋白。我们注意到一个总体趋势，即 MSC 成分更有可能与隐性疾病有关，而独立的 aaRS 主要与显性 CMT 疾病和自身免疫性 ASS 相关。 GlyRS 和 LysRS 似乎更容易受到突变影响，可能是由于它们双重用于细胞质和线粒体蛋白质合成。然而，正如 ASS 和 CMT 的研究表明，aaRS 的非酶功能也与疾病有关。
As an essential component of the translation machinery, aminoacyl-tRNA synthetases (aaRSs) are indispensable for cell viability. In complex multicellular organisms, this fundamental importance of aaRSs is further expanded by their broad regulatory functions, and reflected by their extensive human disease connections. This chapter focuses on the disease connection of the group of aaRSs supporting protein synthesis in the cytoplasm, including GlyRS and LysRS that are also used for mitochondrial translation. To date, three major disease types have been linked directly to cytoplasmic aaRSs: first, an autoimmune antisynthetase syndrome (ASS) characterized by the presence of auto-antibodies targeting one of eight different aaRSs; second, a peripheral neuropathy, Charcot-Marie-Tooth disease (CMT) caused by dominant, mono-allelic mutations in six different aaRSs; and third, severe multi-organ disorders, often accompanied with developmental delays, caused by recessive, bi-allelic mutations in almost all cytoplasmic aaRSs. This chapter will cover broadly each of these types, with a lesser focus on CMT. An interesting feature of cytoplasmic aaRSs in complex organisms is the formation of a multi-synthetase complex (MSC), containing nine aaRSs and three non-enzymatic scaffold proteins. We note a general trend that MSC components are more likely to be involved in recessive diseases, whereas the freestanding aaRSs are predominantly linked to the dominant CMT disease and the autoimmune ASS. GlyRS and LysRS appear to be more susceptive to mutational impact, possibly due to their dual use for cytosolic and mitochondrial protein synthesis. Nevertheless, non-enzymatic functions of aaRSs are also linked to diseases as suggested by studies on ASS and CMT.