Department of Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Nucleic Acids Res. 2019 Oct 10;47(18):9888-9901. doi: 10.1093/nar/gkz732.
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.
tRNA 衍生的 RNA 片段（tRFs）作为一类新的功能 RNA，已被发现在癌症、代谢和神经紊乱以及病毒感染中发挥作用。然而，我们对其生物发生和功能的理解仍然有限。在本研究中，通过对小 RNA 谱的分析，我们在肝癌细胞系 Huh7 中鉴定出了一组独特的来自前 tRNA 3' 尾部的 tRFs。在这些 tRFs 中，tRF_U3_1 是一个 19 个核苷酸长的 chr10.tRNA2-Ser(TGA)-衍生的尾部，在 Huh7 和癌性肝组织中表达最为丰富，主要存在于细胞质中。我们表明，tRF_U3_1 的遗传缺失不会影响细胞生长，也不参与 Ago2 介导的基因沉默。利用 La/SSB 敲除 Huh7 细胞系，我们证明这种核质穿梭蛋白直接结合 tRF_U3_1 的 3' U 尾和其他大量表达的尾部，并在其稳定的细胞质积累中发挥关键作用。能够将有限数量的 La/SSB 隔离在细胞质中的前 tRNA 尾部衍生的 tRFs 使细胞对各种 RNA 病毒具有抗性，这些病毒利用 RNA 伴侣活性夺取 La/SSB 以进行其基因表达。总的来说，我们的结果建立了尾部衍生的 tRF-La/SSB 界面，调节病毒基因表达。
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