Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
Nucleic Acids Res. 2018 Sep 28;46(17):9134-9147. doi: 10.1093/nar/gky575.
Here we show that laboratory of genetics and physiology 2 (LGP2) virus sensor protein regulates gene expression network of endogenous genes mediated by TAR-RNA binding protein (TRBP)-bound microRNAs (miRNAs). TRBP is an enhancer of RNA silencing, and functions to recruit precursor-miRNAs (pre-miRNAs) to Dicer that processes pre-miRNA into mature miRNA. Viral infection activates the antiviral innate immune response in mammalian cells. Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, melanoma-differentiation-associated gene 5 (MDA5), and LGP2, function as cytoplasmic virus sensor proteins during viral infection. RIG-I and MDA5 can distinguish between different types of RNA viruses to produce antiviral cytokines, including type I interferon. However, the role of LGP2 is controversial. We found that LGP2 bound to the double-stranded RNA binding sites of TRBP, resulting in inhibition of pre-miRNA binding and recruitment by TRBP. Furthermore, although it is unclear whether TRBP binds to specific pre-miRNA, we found that TRBP bound to particular pre-miRNAs with common structural characteristics. Thus, LGP2 represses specific miRNA activities by interacting with TRBP, resulting in selective regulation of target genes. Our findings show that a novel function of LGP2 is to modulate RNA silencing, indicating the crosstalk between RNA silencing and RLR signaling in mammalian cells.
在这里，我们展示了实验室遗传学和生理学 2（LGP2）病毒传感器蛋白调节由 TAR-RNA 结合蛋白（TRBP）结合的 microRNAs（miRNAs）介导的内源性基因表达网络。TRBP 是 RNA 沉默的增强子，其功能是招募前体-miRNA（pre-miRNA）到 Dicer，后者将 pre-miRNA 加工成成熟的 miRNA。病毒感染激活哺乳动物细胞中的抗病毒先天免疫反应。视黄酸诱导基因 I（RIG-I）样受体（RLRs），包括 RIG-I、黑色素瘤分化相关基因 5（MDA5）和 LGP2，在病毒感染期间作为细胞质病毒传感器蛋白发挥作用。RIG-I 和 MDA5 可以区分不同类型的 RNA 病毒，产生抗病毒细胞因子，包括 I 型干扰素。然而，LGP2 的作用存在争议。我们发现 LGP2 与 TRBP 的双链 RNA 结合位点结合，导致 pre-miRNA 结合和 TRBP 募集的抑制。此外，尽管不清楚 TRBP 是否结合特定的 pre-miRNA，但我们发现 TRBP 结合具有共同结构特征的特定 pre-miRNA。因此，LGP2 通过与 TRBP 相互作用抑制特定 miRNA 的活性，从而对靶基因进行选择性调节。我们的研究结果表明，LGP2 的一个新功能是调节 RNA 沉默，表明 RNA 沉默和 RLR 信号在哺乳动物细胞中的串扰。
