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CG dinucleotide suppression enables antiviral defence targeting non-self RNA

机译：CG二核苷酸抑制可实现针对非自身RNA的抗病毒防御

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摘要

Vertebrate genomes exhibit marked CG suppression-that is, lower than expected numbers of 5'-CG-3' dinucleotides(1). This feature is likely to be due to C-to-T mutations that have accumulated over hundreds of millions of years, driven by CG-specific DNA methyl transferases and spontaneous methyl-cytosine deamination. Many RNA viruses of vertebrates that are not substrates for DNA methyl transferases mimic the CG suppression of their hosts(2-4). This property of viral genomes is unexplained(4-6). Here we show, using synonymous mutagenesis, that CG suppression is essential for HIV-1 replication. The deleterious effect of CG dinucleotides on HIV-1 replication was cumulative, associated with cytoplasmic RNA depletion, and was exerted by CG dinucleotides in both translated and non-translated exonic RNA sequences. A focused screen using small inhibitory RNAs revealed that zinc-finger antiviral protein (ZAP) 7 inhibited virion production by cells infected with CG-enriched HIV-1. Crucially, HIV-1 mutants containing segments whose CG content mimicked random nucleotide sequence were defective in unmanipulated cells, but replicated normally in ZAP-deficient cells. Crosslinking-immunoprecipitation-sequencing assays demonstrated that ZAP binds directly and selectively to RNA sequences containing CG dinucleotides. These findings suggest that ZAP exploits host CG suppression to identify non-self RNA. The dinucleotide composition of HIV-1, and perhaps other RNA viruses, appears to have adapted to evade this host defence.
机译：脊椎动物基因组显示出显着的CG抑制作用-即低于预期的5'-CG-3'二核苷酸的数量（1）。此功能可能是由于CG特异的DNA甲基转移酶和自发的甲基胞嘧啶脱氨作用驱动的C-T突变积累了数亿年。许多不是DNA甲基转移酶底物的脊椎动物RNA病毒都模仿其宿主的CG抑制（2-4）。病毒基因组的这一特性无法解释（4-6）。在这里，我们使用同义诱变表明，CG抑制对于HIV-1复制至关重要。 CG二核苷酸对HIV-1复制的有害作用是累积性的，与细胞质RNA消耗有关，并由CG二核苷酸在翻译和非翻译外显子RNA序列中发挥作用。使用小的抑制性RNA的集中筛选显示，锌指抗病毒蛋白（ZAP）7抑制了富含CG的HIV-1感染的细胞产生的病毒粒子。至关重要的是，HIV-1突变体的CG含量模仿随机核苷酸序列，其片段在未操纵的细胞中有缺陷，但在ZAP缺陷的细胞中可正常复制。交联免疫沉淀测序测定法表明ZAP直接和选择性地结合包含CG二核苷酸的RNA序列。这些发现表明，ZAP利用宿主CG抑制来鉴定非自身RNA。 HIV-1的二核苷酸组成，也许还有其他RNA病毒，似乎已适应逃避这种宿主防御。

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  • 来源
    《Nature》 |2017年第7674期|124-127|共4页
  • 作者

    Takata Matthew A.; Goncalves-Carneiro Daniel; Zang Trinity M.; Soll Steven J.; York Ashley; Blanco-Melo Daniel; Bieniasz Paul D.;

  • 作者单位

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA;

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA;

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA|Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA;

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA|Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA;

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA;

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA;

    Rockefeller Univ, Lab Retrovirol, 1230 York Ave, New York, NY 10021 USA|Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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