更新于：2024-09-19

RNase L

更新于：2024-09-19

基本信息

别名

2-5A-dependent ribonuclease、2-5A-dependent RNase、PRCA1

+ [5]

简介

Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis (PubMed:26263979). Might play a central role in the regulation of mRNA turnover (PubMed:11585831). Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length.

关联

100 项与 RNase L 相关的临床结果

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100 项与 RNase L 相关的转化医学

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0 项与 RNase L 相关的专利（医药）

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944

项与 RNase L 相关的文献（医药）

2024-12-01·Molecular Biology Reports

Crosstalk between vault RNAs and innate immunity

Review

作者: Martínez-Montero, Juan Pablo ; Avila-Bonilla, Rodolfo Gamaliel

AbstractPurposeVault (vt) RNAs are noncoding (nc) RNAs transcribed by RNA polymerase III (RNA Pol III) with 5ʹ-triphosphate (5ʹ-PPP) termini that play significant roles and are recognized by innate immune sensors, including retinoic acid-inducible protein 1 (RIG-I). In addition, vtRNAs adopt secondary structures that can be targets of interferon-inducible protein kinase R (PKR) and the oligoadenylate synthetase (OAS)/RNase L system, both of which are important for activating antiviral defenses. However, changes in the expression of vtRNAs have been associated with pathological processes that activate proinflammatory pathways, which influence cellular events such as differentiation, aging, autophagy, apoptosis, and drug resistance in cancer cells.ResultsIn this review, we summarized the biology of vtRNAs and focused on their interactions with the innate immune system. These findings provide insights into the diverse roles of vtRNAs and their correlation with various cellular processes to improve our understanding of their biological functions.

2024-09-01·Cell Reports

RNase L-induced bodies sequester subgenomic flavivirus RNAs to promote viral RNA decay

Article

作者: Watkins, J Monty ; Burke, James M

Subgenomic flavivirus RNAs (sfRNAs) are structured RNAs encoded by flaviviruses that promote viral infection by inhibiting cellular RNA decay machinery. Herein, we analyze sfRNA production and localization using single-molecule RNA fluorescence in situ hybridization (smRNA-FISH) throughout West Nile virus, Zika virus, or dengue virus serotype 2 infection. We observe that sfRNAs are generated during the RNA replication phase of viral infection in the cytosol and accumulate in processing bodies (P-bodies), which contain RNA decay machinery such as XRN1 and Dcp1b. However, upon activation of the host antiviral endoribonuclease, ribonuclease L (RNase L), sfRNAs re-localize to ribonucleoprotein complexes known as RNase L-induced bodies (RLBs). RLB-mediated sequestration of sfRNAs reduces sfRNA association with RNA decay machinery in P-bodies, which coincides with increased viral RNA decay. These findings establish a functional role for RLBs in enhancing the cell-mediated decay of viral RNA by sequestering functional viral RNA decay products.

2024-08-07·Journal of the American Chemical Society

Transcriptome-Wide, Unbiased Profiling of Ribonuclease Targeting Chimeras

Article

作者: Disney, Matthew D ; Wang, Tenghui ; Su, Xiaoxuan ; Taghavi, Amirhossein ; Childs-Disney, Jessica L ; Rouse, Warren ; Tong, Yuquan ; Moss, Walter N ; Kovachka, Sandra ; Zanon, Patrick R A

Various approaches have been developed to target RNA and modulate its function with modes of action including binding and cleavage. Herein, we explored how small molecule binding is correlated with cleavage induced by heterobifunctional ribonuclease targeting chimeras (RiboTACs), where RNase L is recruited to cleave the bound RNA target, in a transcriptome-wide, unbiased fashion. Only a fraction of bound targets was cleaved by RNase L, induced by RiboTAC binding. Global analysis suggested that (i) cleaved targets generally form a region of stable structure that encompasses the small molecule binding site; (ii) cleaved targets have preferred RNase L cleavage sites nearby small molecule binding sites; (iii) RiboTACs facilitate a cellular interaction between cleaved targets and RNase L; and (iv) the expression level of the target influences the extent of cleavage observed. In one example, we converted a binder of LGALS1 (galectin-1) mRNA into a RiboTAC. In MDA-MB-231 cells, the binder had no effect on galectin-1 protein levels, while the RiboTAC cleaved LGALS1 mRNA, reduced galectin-1 protein abundance, and affected galectin-1-associated oncogenic cellular phenotypes. Using LGALS1, we further assessed additional factors including the length of the linker that tethers the two components of the RiboTAC, cellular uptake, and the RNase L-recruiting module on RiboTAC potency. Collectively, these studies may facilitate triangulation of factors to enable the design of RiboTACs.

项与 RNase L 相关的新闻（医药）

2023-02-22

·Science Daily

How lung cells protect themselves against RNA viral infection

A new study uncovers how a protein, APOBEC3B, could protects cells against many different types of RNA viruses like respiratory syncytial virus (RSV), SARS-CoV2, influenza virus, poliovirus and measles, helping to prevent disease. A new University of California, Irvine-led study uncovers how a protein, APOBEC3B, could protects cells against many different types of RNA viruses like respiratory syncytial virus (RSV), SARS-CoV2, influenza virus, poliovirus and measles, helping to prevent disease. The study was published in Nature Communications. Titled, "APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection," the study findings provide an understanding of how lung cells, in particular, protect themselves against RNA viral infection. This new discovery is essential to developing future therapies to limit viral infection and improve the health of patients with chronic lung disease. Respiratory syncytial virus (RSV), SARS-CoV2, influenza virus, poliovirus, and measles -- all single-stranded RNA viruses -- are some examples of highly contagious diseases transmitted by respiratory aerosols that commonly infect lung cells. "Patients with chronic lung diseases, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease and interstitial lung diseases, are more susceptible to respiratory lung infections. These viral infections can further contribute to disease progression," said Remi Buisson, PhD, assistant professor in the UCI School of Medicine Department of Biological Chemistry. "An exciting part of our finding fills a critical knowledge gap by illuminating how APOBEC3B can promote innate immune responses in host cells without generating mutations in the virus genomes and promoting viral evolution." In this study, graduate students Lavanya Manjunath and Sunwoo Oh, both at UCI School of Medicine in the Buisson Laboratory, utilized different RNA virus models, including Sendai virus, poliovirus, and Sindbis virus as tools to determine how APOBEC3B regulates innate immune signaling in response to viral infection. Moreover, they found that APOBEC3B is recruited to stress granules through its interaction with PABPC1 to prevent stress granule destabilization and protect mRNAs associated with stress granules from an RNA endonuclease RNase L that cleave RNAs in host cells. "We propose that APOBEC3B, in addition to its canonical role to edit viral genomes, functions with PABPC1 as important innate immunity mediators, protecting cells at different steps of the innate immune response against viral infections," said Buisson. More research is needed to develop strategies to prevent RNA viral infection. "Our next steps are to determine the detailed mechanism of how APOBEC3B recognizes viral genome to promote an innate immune response and prevent viral replication," said Buisson. "The goal is to identify how RNA viruses developed resistance mechanisms to counteract APOBEC3B functions and escape host cell defense." The study was funded by support from the National Institutes of Health.

2022-12-29

·生物谷

Science：首次揭示一些感染了SARS-CoV-2的儿童会患上MIS-C的潜在遗传原因

一项新的研究首次揭示了一些感染了SARS-CoV-2的儿童会患上MIS-C的潜在遗传原因。相关研究结果于2022年12月20日在线发表在Science期刊上。儿童多系统炎症综合征（Multisystem Inflammatory Syndrome in Children, MIS-C）是一种罕见但可能威胁生命的疾病。这种疾病通常在SARS-CoV-2感染大约四周后发生，具有广泛的症状，比如发烧、呕吐和心肌炎，可导致住院治疗。根据美国疾病控制与预防中心（CDC）的最新数字，各州已经报告了大约9000例MIS-C病例，有71例死亡。一项新的研究首次揭示了一些感染了SARS-CoV-2的儿童会患上MIS-C的潜在遗传原因。相关研究结果于2022年12月20日在线发表在Science期刊上，论文标题为“Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children”。这一结果植根于克利夫兰诊所勒纳研究所癌症生物学系的Robert Silverman博士40多年的研究。这项新的研究发现，蛋白OAS和RNase L的基因突变增加了一些免疫细胞类型的炎症反应。这种变化可导致包括心脏、肺部、肾脏和胃肠道在内的多个器官的炎症。在这项研究中，在一小部分MIS-C患儿中发现了突变。 OAS蛋白是由干扰素诱导的，作为对抗病毒的第一道防线。在检测到病毒的双链RNA后，OAS蛋白激活RNase L以防止病毒增殖和扩散。 Silverman博士说，“RNase L就像剪刀一样，切割被翻译成蛋白---包括引起炎症的称为细胞因子的蛋白---的信使RNA（mRNA）。在MIS-C中，这些常染色体隐性突变要么阻止RNase L剪刀的运作（OAS突变），要么阻止RNase L剪刀的产生（RNase L突变）。这些发现提供了关于OAS-RNase L如何预防这种严重的无法解释的COVID-19并发症的重要见解。” Silverman博士的实验室研究干扰素在免疫反应中的作用，着重关注OAS-RNase L途径。Silverman团队与洛克菲勒大学的Jean-Laurent Casanova医学博士及其团队合作，部分上通过分析MIS-C患者的DNA序列数据，与其他感染了SARS-CoV-2但没有患上MIS-C的儿童进行对比，发现了这些突变。 MIS-C患者的OAS1, OAS2和RNASEL双等位基因变异。图片来自Science, 2022, doi:10.1126/science.abo3627。 Casanova博士说，“我们的发现通过阐明MIS-C的分子、细胞和免疫学基础，提高了对这种疾病的认识。我们通过分析MIS-C患者的DNA序列数据，与其他感染了SARS-CoV-2但没有患上MIS-C的儿童进行比较，确定了这些突变。其中一个关键的研究问题是，在携带这些突变的病例中，是病毒增殖增加还是过度的炎症反应导致了MIS-C。我们的结果支持了后一种解释。” 作为国际合作的一部分，Casanova团队确定了这些突变对OAS-RNase L途径的具体影响。这包括筛选几十个突变基因，确定对RNA的影响，然后将这些结果与这种疾病联系起来。 Silverman博士说，“我们的团队利用我多年来对这两种酶的了解来获得这项研究需要的功能数据。本质上，这验证了这些突变对功能的影响。” Silverman博士的实验室还贡献了非商业化的试剂，合成了一种激活RNase L并使它裂解RNA的小分子。这项研究确定这些突变在分子水平上导致了炎症反应的加剧。有关这些突变以及它们如何影响免疫机制的知识可能为其他导致慢性炎症的疾病提供更多信息，比如临床表现与MIS-C相似的川崎病。（生物谷 Bioon.com）参考资料： 1. Robert Silverman et al. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children. Science, 2022, doi:10.1126/science.abo3627. 2. Research identifies potential genetic cause for MIS-C complication following COVID-19 infectionhttps://medicalxpress.com/news/2022-12-potential-genetic-mis-c-complication-covid-.html

信使RNA临床结果

2022-12-28

·生物谷

Science：首次揭示一些感染了新冠病毒的儿童会患上MIS-C的潜在遗传原因

儿童多系统炎症综合征（Multisystem Inflammatory Syndrome in Children, MIS-C）是一种罕见但可能威胁生命的疾病。这种疾病通常在新冠病毒感染大约四周后发生，引起比如发烧、呕吐和心肌炎等症状，可导致住院治疗。根据美国疾病控制与预防中心（CDC）的最新数字，各州已经报告了大约9000例MIS-C病例，有71例死亡。一项新的研究首次揭示了一些感染了新冠病毒的儿童会患上MIS-C的潜在遗传原因。相关研究结果于2022年12月20日在线发表在Science期刊上，论文标题为“Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children”。这一结果植根于克利夫兰诊所勒纳研究所癌症生物学系的Robert Silverman博士40多年的研究。这项新的研究发现，蛋白OAS和RNase L的基因突变增加了一些免疫细胞类型的炎症反应。这种变化可导致包括心脏、肺部、肾脏和胃肠道在内的多个器官的炎症。在这项研究中，在一小部分MIS-C患儿中发现了突变。OAS蛋白是由干扰素诱导的，作为对抗病毒的第一道防线。在检测到病毒的双链RNA后，OAS蛋白激活RNase L以防止病毒增殖和扩散。Silverman博士说，“RNase L就像剪刀一样，切割被翻译成蛋白---包括引起炎症的称为细胞因子的蛋白---的信使RNA（mRNA）。在MIS-C中，这些常染色体隐性突变要么阻止RNase L剪刀的运作（OAS突变），要么阻止RNase L剪刀的产生（RNase L突变）。这些发现提供了关于OAS-RNase L如何预防这种严重的无法解释的COVID-19并发症的重要见解。”Silverman博士的实验室研究干扰素在免疫反应中的作用，着重关注OAS-RNase L途径。Silverman团队与洛克菲勒大学的Jean-Laurent Casanova医学博士及其团队合作，部分上通过分析MIS-C患者的DNA序列数据，与其他感染了新冠病毒但没有患上MIS-C的儿童进行对比，发现了这些突变。MIS-C患者的OAS1, OAS2和RNASEL双等位基因变异。图片来自Science, 2022, doi:10.1126/science.abo3627。Casanova博士说，“我们的发现通过阐明MIS-C的分子、细胞和免疫学基础，提高了对这种疾病的认识。我们通过分析MIS-C患者的DNA序列数据，与其他感染了新冠病毒但没有患上MIS-C的儿童进行比较，确定了这些突变。其中一个关键的研究问题是，在携带这些突变的病例中，是病毒增殖增加还是过度的炎症反应导致了MIS-C。我们的结果支持了后一种解释。”作为国际合作的一部分，Casanova团队确定了这些突变对OAS-RNase L途径的具体影响。这包括筛选几十个突变基因，确定对RNA的影响，然后将这些结果与这种疾病联系起来。Silverman博士说，“我们的团队利用我多年来对这两种酶的了解来获得这项研究需要的功能数据。本质上，这验证了这些突变对功能的影响。”Silverman博士的实验室还贡献了非商业化的试剂，合成了一种激活RNase L并使它裂解RNA的小分子。这项研究确定这些突变在分子水平上导致了炎症反应的加剧。有关这些突变以及它们如何影响免疫机制的知识可能为其他导致慢性炎症的疾病提供更多信息，比如临床表现与MIS-C相似的川崎病。参考资料：1. Robert Silverman et al. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children. Science, 2022, doi:10.1126/science.abo3627.2. Research identifies potential genetic cause for MIS-C complication following COVID-19 infectionhttps://medicalxpress.com/news/2022-12-potential-genetic-mis-c-complication-covid-.html

信使RNA基因疗法