PDF(Pubmed)
Abstract：
RNA processing is a highly conserved mechanism that serves as a pivotal regulator of gene expression. Alternative processing generates transcripts that can still be translated but lead to potentially nonfunctional proteins. A plethora of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strategically manipulate the host\'s RNA processing machinery to circumvent antiviral responses. We integrated publicly available omics datasets to systematically analyze isoform-level expression and delineate the nascent peptide landscape of SARS-CoV-2-infected human cells. Our findings explore a suggested but uncharacterized mechanism, whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling, interferon-stimulated (ISGs), class I MHC, and splicing machinery genes, including IRF7, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6 and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs an unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.
摘要：
RNA加工是一种高度保守的机制，可作为基因表达的关键调节剂。替代加工产生仍然可以翻译但导致潜在非功能性蛋白质的转录本。大量的呼吸道病毒,包括严重急性呼吸道综合症冠状病毒2（SARS-CoV-2），战略性地操纵宿主的RNA加工机制来规避抗病毒反应。我们整合了公开可用的组学数据集以系统分析同工型水平的表达，并描绘了SARS-CoV-2感染的人类细胞的新生肽景观。我们的发现探索了一种建议但未表征的机制，SARS-CoV-2感染诱导关键IFN信号中非生产性剪接同工型的主要表达，干扰素刺激（ISG），I类MHC,和剪接机制基因，包括IRF7HLA-B,HNRNPH1与之形成鲜明对比的是,细胞因子和趋化因子基因，如IL6和TNF，主要表达对SARS-CoV-2感染的生产性（蛋白质编码）剪接同工型。我们假设SARS-CoV-2采用了一种未报道的策略，即利用宿主剪接机制来增强病毒复制并通过选择性地上调来自抗原呈递和抗病毒反应基因的非生产性剪接亚型来破坏免疫反应。我们的研究揭示了SARS-CoV-2与宿主免疫系统之间的分子相互作用，为开发新的对抗COVID-19的治疗策略奠定了基础。
