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Adenovirus prevents dsRNA formation by promoting efficient splicing of viral RNA
Nucleic Acids Research ( IF 14.9 ) Pub Date : 2021-10-08 , DOI: 10.1093/nar/gkab896 Alexander M Price 1 , Robert T Steinbock 1, 2 , Chao Di 3 , Katharina E Hayer 3 , Yize Li 4 , Christin Herrmann 1, 2 , Nicholas A Parenti 4 , Jillian N Whelan 4 , Susan R Weiss 4 , Matthew D Weitzman 1, 5
Nucleic Acids Research ( IF 14.9 ) Pub Date : 2021-10-08 , DOI: 10.1093/nar/gkab896 Alexander M Price 1 , Robert T Steinbock 1, 2 , Chao Di 3 , Katharina E Hayer 3 , Yize Li 4 , Christin Herrmann 1, 2 , Nicholas A Parenti 4 , Jillian N Whelan 4 , Susan R Weiss 4 , Matthew D Weitzman 1, 5
Affiliation
Eukaryotic cells recognize intracellular pathogens through pattern recognition receptors, including sensors of aberrant nucleic acid structures. Sensors of double-stranded RNA (dsRNA) are known to detect replication intermediates of RNA viruses. It has long been suggested that annealing of mRNA from symmetrical transcription of both top and bottom strands of DNA virus genomes can produce dsRNA during infection. Supporting this hypothesis, nearly all DNA viruses encode inhibitors of dsRNA-recognition pathways. However, direct evidence that DNA viruses produce dsRNA is lacking. Contrary to dogma, we show that the nuclear-replicating DNA virus adenovirus (AdV) does not produce detectable levels of dsRNA during infection. In contrast, abundant dsRNA is detected within the nucleus of cells infected with AdV mutants defective for viral RNA processing. In the presence of nuclear dsRNA, the cytoplasmic dsRNA sensor PKR is relocalized and activated within the nucleus. Accumulation of viral dsRNA occurs in the late phase of infection, when unspliced viral transcripts form intron/exon base pairs between top and bottom strand transcripts. We propose that DNA viruses actively limit dsRNA formation by promoting efficient splicing and mRNA processing, thus avoiding detection and restriction by host innate immune sensors of pathogenic nucleic acids.
中文翻译:
腺病毒通过促进病毒 RNA 的有效剪接来防止 dsRNA 的形成
真核细胞通过模式识别受体识别细胞内病原体,包括异常核酸结构的传感器。已知双链 RNA (dsRNA) 传感器可检测 RNA 病毒的复制中间体。长期以来,人们一直认为,从 DNA 病毒基因组的顶部和底部链的对称转录中退火的 mRNA 可以在感染期间产生 dsRNA。支持这一假设,几乎所有 DNA 病毒都编码 dsRNA 识别途径的抑制剂。然而,缺乏 DNA 病毒产生 dsRNA 的直接证据。与教条相反,我们表明核复制 DNA 病毒腺病毒 (AdV) 在感染期间不会产生可检测水平的 dsRNA。相比之下,在感染了病毒 RNA 加工缺陷的 AdV 突变体的细胞核内检测到丰富的 dsRNA。在存在核 dsRNA 的情况下,细胞质 dsRNA 传感器 PKR 在细胞核内重新定位和激活。病毒 dsRNA 的积累发生在感染的后期,此时未剪接的病毒转录物在顶部和底部链转录物之间形成内含子/外显子碱基对。我们建议 DNA 病毒通过促进有效的剪接和 mRNA 加工来主动限制 dsRNA 的形成,从而避免宿主先天免疫传感器对致病核酸的检测和限制。
更新日期:2021-10-08
中文翻译:
腺病毒通过促进病毒 RNA 的有效剪接来防止 dsRNA 的形成
真核细胞通过模式识别受体识别细胞内病原体,包括异常核酸结构的传感器。已知双链 RNA (dsRNA) 传感器可检测 RNA 病毒的复制中间体。长期以来,人们一直认为,从 DNA 病毒基因组的顶部和底部链的对称转录中退火的 mRNA 可以在感染期间产生 dsRNA。支持这一假设,几乎所有 DNA 病毒都编码 dsRNA 识别途径的抑制剂。然而,缺乏 DNA 病毒产生 dsRNA 的直接证据。与教条相反,我们表明核复制 DNA 病毒腺病毒 (AdV) 在感染期间不会产生可检测水平的 dsRNA。相比之下,在感染了病毒 RNA 加工缺陷的 AdV 突变体的细胞核内检测到丰富的 dsRNA。在存在核 dsRNA 的情况下,细胞质 dsRNA 传感器 PKR 在细胞核内重新定位和激活。病毒 dsRNA 的积累发生在感染的后期,此时未剪接的病毒转录物在顶部和底部链转录物之间形成内含子/外显子碱基对。我们建议 DNA 病毒通过促进有效的剪接和 mRNA 加工来主动限制 dsRNA 的形成,从而避免宿主先天免疫传感器对致病核酸的检测和限制。