Regulation of La/SSB-dependent viral gene expression by pre-tRNA 3′ trailer-derived tRNA fragments
Regulation of La/SSB-dependent viral gene expression by pre-tRNA 3′ trailer-derived tRNA fragments
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DOI：
10.1093/nar/gkz732
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发表时间：
2019-10-10
影响因子：
14.9
通讯作者：
Oh, Jong-Won
中科院分区：
文献类型：
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作者：
Cho, Hee;Lee, Wooseong;Oh, Jong-Won
tRNA衍生的RNA片段（tRFs）已经作为一类新的功能性RNA出现，其与癌症、代谢和神经系统疾病以及病毒感染有关。然而，我们对它们的生物起源和功能的理解仍然有限。在本研究中，通过分析小RNA谱，我们在肝细胞癌细胞系Huh 7中鉴定了一组来自前tRNA 3'末端的不同tRF。在这些tRF中，tRF_U3_1是一个19个核苷酸长的chr10.tRNA2-Ser（TGA）衍生的trailer，在Huh 7和癌性肝组织中表达最丰富，主要存在于细胞质中。我们发现tRF_U3_1的遗传丢失不影响细胞生长，并且不参与Ago 2介导的基因沉默。使用La/SSB敲除Huh 7细胞系，我们证明了这种核质穿梭蛋白直接结合tRF_U3_1和其他大量表达的尾部的3'U-尾，并在其稳定的细胞质积累中起关键作用。前-tRNA trailer-derived tRF能够隔离有限数量的La/SSB在细胞质中呈现细胞抵抗各种RNA病毒，其篡夺La/SSB与RNA伴侣活性，用于其基因表达。总的来说，我们的研究结果建立了trailer-derived tRF-La/SSB界面，调节病毒基因表达。
tRNA-derived RNA fragments (tRFs) have emerged as a new class of functional RNAs implicated in cancer, metabolic and neurological disorders, and viral infection. Yet our understanding of their biogenesis and functions remains limited. In the present study, through analysis of small RNA profile we have identified a distinct set of tRFs derived from pre-tRNA 3' trailers in the hepatocellular carcinoma cell line Huh7. Among those tRFs, tRF_U3_1, which is a 19-nucleotide-long chr10.tRNA2-Ser(TGA)-derived trailer, was expressed most abundantly in both Huh7 and cancerous liver tissues, being present primarily in the cytoplasm. We show that genetic loss of tRF_U3_1 does not affect cell growth and it is not involved in Ago2-mediated gene silencing. Using La/SSB knockout Huh7 cell lines, we demonstrate that this nuclear-cytoplasmic shuttling protein directly binds to the 3' U-tail of tRF_U3_1 and other abundantly expressed trailers and plays a critical role in their stable cytoplasmic accumulation. The pre-tRNA trailer-derived tRFs capable of sequestering the limiting amounts of La/SSB in the cytoplasm rendered cells resistant to various RNA viruses, which usurp La/SSB with RNA chaperone activity for their gene expression. Collectively, our results establish the trailer-derived tRF-La/SSB interface, regulating viral gene expression.