Control of antiviral immunity by RNA decay

通过RNA衰变控制抗病毒免疫

• 批准号: 9168153
• 负责人: Ian J Mohr
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9168153
• 关键词: Autoimmune Diseases; Binding; Biology; Cell Nucleus; Cells; Data; Detection; Double-Stranded RNA; Encephalitis; Endoribonucleases; Enzymes; Exonuclease; Generations; Genetic; Herpesviridae; Herpesvirus 1; Host Defense; Human; Immune; Immune response; Infection; Interferon Activation; Life; Measures; Messenger RNA; Mining; Molecular; Nucleic Acids; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphotransferases; Poxviridae; Production; Protein Biosynthesis; Protein Dephosphorylation; Protein Synthesis Inhibition; Proteins; RNA Decay; Reporting; Ribonucleases; Role; Signal Transduction; Skin; Testing; Translations; Vaccinia; Vaccinia virus; Viral; Viral Genes; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; antiviral immunity; base; cellular targeting; decapping enzyme; insight; mutant; pathogen; prevent; research study; response

PROJECT SUMMARY To efficiently multiply in their hosts, viruses must hijack the host protein synthesis machinery and overcome potent cell-intrinsic, anti-viral immune responses. A powerful common strategy utilized by many different patho- genic human viruses to achieve these ends involves accelerating global mRNA decay. Until recently, this has been regarded primarily as a means to restrict production of host anti-viral proteins, promote translation of abundant viral mRNAs, and facilitate transitions between different temporal classes of viral mRNAs. In cells infected with the prototypical poxvirus Vaccinia, global mRNA decay is stimulated by viral decapping enzymes that presumably generate substrates for degradation by the cellular 5'-3' mRNA exonuclease Xrn1. Unexpect- edly, our preliminary results demonstrated that the host Xrn1 is required to limit accumulation of double- stranded RNA (dsRNA), a pathogen-associated molecular pattern (PAMP) that activates host anti-viral defen- ses and results in inhibition of protein synthesis and viral replication. Moreover, Xrn1-depletion sensitized uninfected cells to exogenous dsRNA, excluding the possibility that the response is specific to Vaccinia- encoded dsRNA. This raises the exciting possibility that other viruses liable to generate dsRNA may rely on Xrn1 function to avoid immune detection. Our overall objective is to understand how cell intrinsic antiviral immunity is controlled by host RNA decay enzymes. Unlike Vaccinia virus, herpes simplex virus-1 (HSV1) replicates in the nucleus and does not encode decapping enzymes. Importantly, cytoplasmic dsRNA reportedly accumulates in HSV1-infected cells and global mRNA decay is accelerated via the virus-encoded vhs mRNA endonuclease. Endonucleolytic mRNA cleavage by vhs produces substrates with 5'-monophosphate termini that are substrates for Xrn1, although the role of Xrn1 in HSV1 infection biology remains largely unknown. Based on our preliminary data, we hypothesize that the host mRNA decay enzyme Xrn1 regulates cytoplasmic dsRNA accumulation in HSV1-infected cells. Here, this hypothesis is tested in two specific aims that i) deter- mine the role of the 5'-3' mRNA exonuclease Xrn1 in HSV-1 infection biology; and ii) define how the HSV1 mRNA endonuclease vhs collaborates with Xrn1 to regulate dsRNA abundance and anti-viral immune respons- es. Results from these experiments will impact our understanding of how host mRNA decay enzymes regulate cell intrinsic anti-viral immunity in cells infected with the human herpesvirus HSV1. Furthermore, investigating how Xrn1 regulates dsRNA accumulation and anti-viral immunity are potentially applicable to a wide variety of pathogenic human viruses and could reveal new strategies for treating virus infections. Finally, this study will provide insight into how cellular mRNA decay enzymes regulate nucleic acid-responsive, cell intrinsic immune pathways and have significant implications for understanding both autoimmune disease and infection biology.

项目摘要 要有效地繁殖宿主，病毒必须劫持宿主蛋白质合成机制并克服 有效的细胞中性，抗病毒免疫反应。许多不同的病情使用的强大共同策略 实现这些目的的基因人类病毒涉及加速全球mRNA衰变。直到最近， 被视为限制宿主抗病毒蛋白的产生的一种手段，促进 丰富的病毒mRNA，并促进了不同时间类别的病毒mRNA之间的过渡。在细胞中 被原型痘病毒疫苗感染，全局mRNA衰变受到病毒式腐蚀酶的刺激 大概会产生细胞5'-3'mRNA外切核酸酶XRN1降解的底物。不期望 埃德利（Edly 滞留的RNA（DSRNA），一种与病原体相关的分子模式（PAMP），激活宿主的抗病毒防御 SES和结果抑制蛋白质合成和病毒复制。此外，XRN1消耗敏化 未感染的细胞对外源性dsRNA，不包括响应特定于售票的可能性 编码的dsRNA。这增加了其他病毒可能产生dsRNA的激动人心的可能性 XRN1功能避免免疫检测。我们的总体目标是了解细胞内在的抗病毒 免疫力受宿主RNA衰减酶的控制。与离甲酸病毒不同，单纯疱疹病毒1（HSV1） 在细胞核中复制，不编码解替酶。重要的是，据报道，细胞质dsRNA 通过病毒编码的VHS mRNA加速HSV1感染的细胞和全局mRNA衰变的积累 核酸内切酶。 VHS的内核水解mRNA裂解可产生5'Oonophophate末端的底物 这是XRN1的底物，尽管XRN1在HSV1感染生物学中的作用在很大程度上仍然未知。 根据我们的初步数据，我们假设宿主mRNA衰变酶XRN1调节细胞质 DSRNA在HSV1感染的细胞中的积累。在这里，该假设以两个具体目的进行了检验，即 挖掘5'-3'mRNA外切核酸酶XRN1在HSV-1感染生物学中的作用； ii）定义HSV1如何 mRNA核酸内切酶VHS与XRN1合作以调节DSRNA丰度和抗病毒免疫反应 - es。这些实验的结果将影响我们对宿主mRNA衰减酶调节的理解 感染人类疱疹病毒HSV1的细胞中的细胞内在抗病毒免疫。此外，调查 XRN1如何调节DSRNA的积累和抗病毒免疫力可能适用于多种 致病性人类病毒，可以揭示治疗病毒感染的新策略。最后，这项研究将 提供有关细胞mRNA衰减酶如何调节核酸反应性，细胞内在免疫的见解 途径，对理解自身免疫性疾病和感染生物学具有重要意义。