Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs
Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs
复制标题
血管生成素通过将 tRNA 切割成 tiRNA 来防止颗粒蛋白前体 A9D 突变诱导的神经元样细胞凋亡
DOI：
10.1007/s12035-017-0396-7
复制
发表时间：
2018-02-01
影响因子：
5.1
通讯作者：
Xu, Zhengping
中科院分区：
文献类型：
--
作者：
Li, Siqi;Chen, Yongdui;Xu, Zhengping
基因缺陷已被认为是神经退行性变的病因和发病机制中的突出因素。在60个神经变性相关的颗粒蛋白前体（PGRN）突变中，PGRN基因外显子1的突变在其信号肽的疏水核心的残基9处引入了一个带电氨基酸（命名为PGRN A9 D），并导致不正确的细胞质分选。然而，这种突变的发病机制仍然难以捉摸。为了解决这个问题，我们首先检查了PGRN A9 D在人神经元样细胞（SH-SY 5 Y）中的亚细胞分布。结果表明，PGRN A9 D在胞质应激颗粒中积累。有趣的是，这种错误分选与血管生成素（ANG）（一种应激反应因子和神经退行性疾病相关蛋白）从细胞核到细胞质应激颗粒的细胞再分布有关，并且PGRN A9 D和ANG之间存在蛋白质相互作用。进一步的研究表明PGRN A9 D的应激颗粒定位依赖于ANG。在功能上，PGRN A9 D消除了核ANG介导的生物学作用;另一方面，ANG重新定位至应激颗粒通过将转移RNA（tRNA）切割成tiRNA（tRNA衍生的应激诱导的小RNA）激活其细胞保护性应激反应程序，从而促进PGRN A9 D细胞存活。综上所述，我们假设PGRN A9 D导致ANG保留在细胞质中以保护细胞免受PGRN A9 D诱导的细胞凋亡，这意味着PGRN和ANG协同作用以调节神经退行性疾病的进展。
Gene defects have been recognized as prominent factors in the etiology and pathogenesis of neurodegeneration. Among 60 neurodegeneration-related mutations in progranulin (PGRN), a mutation in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of its signal peptide at residue 9 (named PGRN A9D) and results in incorrect cytoplasmic sorting. However, the pathogenesis of this mutation remains elusive. To address this issue, we first examined the subcellular distribution of PGRN A9D in human neuronal-like cells (SH-SY5Y). The results showed that PGRN A9D accumulated in cytosolic stress granules. Interestingly, this mis-sorting associated with a cellular redistribution of angiogenin (ANG), a stress-response factor and neurodegenerative disease-related protein, from nucleus to cytoplasmic stress granules, and there existed protein interaction between PGRN A9D and ANG. Further study revealed that the stress granule localization of PGRN A9D was dependent on ANG. Functionally, PGRN A9D abolished the nuclear ANG-mediated biological roles; on the other hand, the relocation of ANG to stress granules activated its cytoprotective stress-response program by cleaving transfer RNAs (tRNAs) to tiRNAs (tRNA-derived, stress-induced small RNAs), thus promoting PGRN A9D cell survival. Taken together, we hypothesize that PGRN A9D leads to the retention of ANG in the cytoplasm to protect cells from PGRN A9D-induced apoptosis, implying that PGRN and ANG act in concert to regulate the progress of neurodegenerative disease.