Tyrosine pre-transfer RNA fragments are linked to p53-dependent neuronal cell death via PKM2
Tyrosine pre-transfer RNA fragments are linked to p53-dependent neuronal cell death via PKM2
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DOI：
10.1016/j.bbrc.2020.02.157
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发表时间：
2020-05-07
影响因子：
3.1
通讯作者：
Hanada, Toshikatsu
中科院分区：
文献类型：
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作者：
Inoue, Masanori;Hada, Kazumasa;Hanada, Toshikatsu
转移核糖核酸(TRNA)片段来源于前tRNA或成熟tRNA，已被发现在神经退行性疾病等多种疾病的发病机制中发挥重要作用。CLP1是一种参与tRNA生物发生的RNA激酶，其编码基因的突变与桥小脑发育不全10型有关。CLP1基因的突变会导致几种不同类型的tRNA片段的积累。这些tRNA片段有望与该病的发病机制相关。然而，目前尚不清楚CLP1基因突变产生的哪种tRNA片段对神经性疾病的发病影响最大。我们发现，来源于酪氨酸前体tRNA(5‘Tyr-TRF)的5’tRNA片段比其他类型的tRNA片段更能引起p53依赖的神经细胞死亡。我们还发现5‘Tyr-TRF与丙酮酸激酶M2(PKM2)直接结合。注射PKM2基因的斑马鱼胚胎可改善5‘Tyr-TRF诱导的斑马鱼胚胎神经元缺陷。我们的发现部分揭示了5‘Tyr-TRF和受PKM2调控的神经细胞死亡之间的机制联系。(C)2020 Elsevier Inc.保留所有权利。
Fragments of transfer RNA (tRNA), derived either from pre-tRNA or mature tRNA, have been discovered to play an essential role in the pathogenesis of various disorders such as neurodegenerative disease. CLP1 is an RNA kinase involved in tRNA biogenesis, and mutations in its encoding gene are responsible for pontocerebellar hypoplasia type-10. Mutation of the CLP1 gene results in the accumulation of tRNA fragments of several different kinds. These tRNA fragments are expected to be associated with the disease pathogenesis. However, it is still unclear which of the tRNA fragments arising from the CLP1 gene mutation has the greatest impact on the onset of neuronal disease. We found that 5' tRNA fragments derived from tyrosine pre-tRNA (5' Tyr-tRF) caused p53-dependent neuronal cell death predominantly more than other types of tRNA fragment. We also showed that 5' Tyr-tRF bound directly to pyruvate kinase M2 (PKM2). Injection of zebrafish embryos with PKM2 mRNA ameliorated the neuronal defects induced in zebrafish embryos by 5' Tyr-tRF. Our findings partially uncovered a mechanistic link between 5' Tyr-tRF and neuronal cell death that is regulated by PKM2. (C) 2020 Elsevier Inc. All rights reserved.