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宿主样 RNA 元件调节病毒翻译。

Host-like RNA Elements Regulate Virus Translation.

机构信息

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

出版信息

Viruses. 2024 Mar 20;16(3):468. doi: 10.3390/v16030468.

Abstract

Viruses are obligate, intracellular parasites that co-opt host cell machineries for propagation. Critical among these machineries are those that translate RNA into protein and their mechanisms of control. Most regulatory mechanisms effectuate their activity by targeting sequence or structural features at the RNA termini, i.e., at the 5' or 3' ends, including the untranslated regions (UTRs). Translation of most eukaryotic mRNAs is initiated by 5' cap-dependent scanning. In contrast, many viruses initiate translation at internal RNA regions at internal ribosome entry sites (IRESs). Eukaryotic mRNAs often contain upstream open reading frames (uORFs) that permit condition-dependent control of downstream major ORFs. To offset genome compression and increase coding capacity, some viruses take advantage of out-of-frame overlapping uORFs (oORFs). Lacking the essential machinery of protein synthesis, for example, ribosomes and other translation factors, all viruses utilize the host apparatus to generate virus protein. In addition, some viruses exhibit RNA elements that bind host regulatory factors that are not essential components of the translation machinery. SARS-CoV-2 is a paradigm example of a virus taking advantage of multiple features of eukaryotic host translation control: the virus mimics the established human GAIT regulatory element and co-opts four host aminoacyl tRNA synthetases to form a stimulatory binding complex. Utilizing discontinuous transcription, the elements are present and identical in all SARS-CoV-2 subgenomic RNAs (and the genomic RNA). Thus, the virus exhibits a post-transcriptional regulon that improves upon analogous eukaryotic regulons, in which a family of functionally related mRNA targets contain elements that are structurally similar but lacking sequence identity. This "thrifty" virus strategy can be exploited against the virus since targeting the element can suppress the expression of all subgenomic RNAs as well as the genomic RNA. Other 3' end viral elements include 3'-cap-independent translation elements (3'-CITEs) and 3'-tRNA-like structures. Elucidation of virus translation control elements, their binding proteins, and their mechanisms can lead to novel therapeutic approaches to reduce virus replication and pathogenicity.

摘要

病毒是专性的、细胞内寄生虫,它们利用宿主细胞机制进行繁殖。在这些机制中,翻译 RNA 为蛋白质的机制及其调控机制至关重要。大多数调控机制通过靶向 RNA 末端(即 5' 或 3' 端)的序列或结构特征来实现其活性,包括非翻译区 (UTR)。大多数真核 mRNA 的翻译是通过 5' 帽依赖性扫描起始的。相比之下,许多病毒在内部核糖体进入位点 (IRES) 处的内部 RNA 区域起始翻译。真核 mRNA 通常含有上游开放阅读框 (uORF),允许对下游主要 ORF 进行条件依赖性控制。为了弥补基因组压缩并增加编码能力,一些病毒利用框架外重叠的 uORF (oORF)。由于缺乏蛋白质合成的基本机制,例如核糖体和其他翻译因子,所有病毒都利用宿主设备来产生病毒蛋白。此外,一些病毒表现出与宿主调节因子结合的 RNA 元件,而这些调节因子不是翻译机制的必需成分。SARS-CoV-2 是病毒利用真核宿主翻译控制的多种特征的范例:病毒模拟了已建立的人类 GAIT 调节元件,并利用四种宿主氨酰-tRNA 合成酶形成一个刺激结合复合物。利用不连续转录,这些元件存在于所有 SARS-CoV-2 亚基因组 RNA(和基因组 RNA)中,并且完全相同。因此,病毒表现出一种转录后调控物,它改进了类似的真核调控物,其中一系列功能相关的 mRNA 靶标包含结构相似但缺乏序列同一性的元件。这种“节俭”的病毒策略可以被利用来对抗病毒,因为靶向该元件可以抑制所有亚基因组 RNA 以及基因组 RNA 的表达。其他 3' 端病毒元件包括 3'-帽非依赖性翻译元件 (3'-CITE) 和 3'-tRNA 样结构。阐明病毒翻译调控元件、它们的结合蛋白及其机制可以为减少病毒复制和致病性提供新的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74b0/10976276/4641bdc7f5e7/viruses-16-00468-g001.jpg

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