Das S, Ott M, Yamane A, Venkatesan A, Gupta S, Dasgupta A
Department of Microbiology, Molecular Genetics and Immunology, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747, USA.
Front Biosci. 1998 Dec 1;3:D1241-52. doi: 10.2741/a359.
The observation that poliovirus mRNA is not translated in the yeast Saccharomyces cerevisiae has led to the discovery of a small RNA (60 nt, called IRNA, inhibitor RNA) which was later shown to specifically inhibit internal ribosome entry site (IRES)-mediated translation of naturally uncapped mRNAs. Translation of cellular capped mRNAs was not significantly inhibited by IRNA. IRNA also specifically inhibited hepatitis C virus (HCV) IRES-mediated translation in vitro and in vivo. A hepatoma cell line constitutively expressing IRNA was refractory to infection by a chimeric poliovirus (PV/HCV) in which PV IRES is replaced by HCV-IRES. In contrast, a PV/EMCV chimeric virus containing the EMCV IRES was not significantly inhibited in the IRNA-hepatoma cell line compared to the control hepatoma cells. UV-crosslinking studies showed that the IRNA binds a number of cellular proteins that appear to be important for IRES-mediated translation. Interaction of these proteins with the viral IRES elements is believed to be important in recruiting ribosomes to the 5( UTR of viral RNAs. The binding of the purified La autoantigen to the HCV IRES element was efficiently and specifically competed by IRNA. These results provide a basis for development of novel drugs effective against HCV infection.
脊髓灰质炎病毒mRNA在酿酒酵母中不进行翻译这一现象，促使人们发现了一种小RNA（60个核苷酸，称为IRNA，即抑制性RNA），后来发现它能特异性抑制内部核糖体进入位点（IRES）介导的天然无帽mRNA的翻译。细胞帽状mRNA的翻译并未受到IRNA的显著抑制。IRNA在体外和体内也能特异性抑制丙型肝炎病毒（HCV）IRES介导的翻译。一种组成性表达IRNA的肝癌细胞系对嵌合脊髓灰质炎病毒（PV/HCV，其中PV的IRES被HCV-IRES取代）的感染具有抗性。相比之下，与对照肝癌细胞相比，含有EMCV IRES的PV/EMCV嵌合病毒在IRNA-肝癌细胞系中并未受到显著抑制。紫外线交联研究表明，IRNA能结合多种细胞蛋白，这些蛋白似乎对IRES介导的翻译很重要。这些蛋白与病毒IRES元件的相互作用被认为在将核糖体招募到病毒RNA的5′UTR中起重要作用。纯化的La自身抗原与HCV IRES元件的结合能被IRNA有效且特异性地竞争。这些结果为开发有效对抗HCV感染的新型药物提供了依据。
