严重急性呼吸系统综合征冠状病毒2型核衣壳蛋白通过RNA结合结构域N2b抑制PKR介导的整合应激反应。

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-22 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011582
Chiara Aloise, Jelle G Schipper, Arno van Vliet, Judith Oymans, Tim Donselaar, Daniel L Hurdiss, Raoul J de Groot, Frank J M van Kuppeveld
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引用次数: 0

摘要

严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)的核衣壳蛋白N包裹并浓缩病毒基因组进行包装,但也是先天抗病毒防御的拮抗剂。据称,它通过与应激颗粒(SG)组装因子G3BP1和2相互作用来抑制整合应激反应(ISR),并抑制I型干扰素反应。为了阐明其作用模式,我们系统地删除并过度表达了不同的区域和领域。我们发现N通过结构域N2b阻断PKR介导的ISR激活,通过抑制ISR诱导的翻译停滞和SG形成来测量。当引入完整的N蛋白时,阻止dsRNA结合的N2b突变也消除了这些活性。据报道,阻断N翻译后修饰或其与G3BP1/2相互作用的取代没有可检测的加性效应。在基于脑心肌炎病毒的感染模型中,N2b(但不是RNA结合缺陷的衍生物)阻止PKR激活,抑制β-干扰素表达并促进病毒复制。显然,严重急性呼吸系统综合征冠状病毒2 N通过隔离dsRNA来阻止PKR和RIG-I样受体的激活,从而抑制先天免疫。对人类冠状病毒229E的N蛋白也进行了类似的观察,表明这可能是其他原冠状病毒(亚)属成员中保守的一个一般特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.

SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.

SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.

SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.

The nucleocapsid protein N of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enwraps and condenses the viral genome for packaging but is also an antagonist of the innate antiviral defense. It suppresses the integrated stress response (ISR), purportedly by interacting with stress granule (SG) assembly factors G3BP1 and 2, and inhibits type I interferon responses. To elucidate its mode of action, we systematically deleted and over-expressed distinct regions and domains. We show that N via domain N2b blocks PKR-mediated ISR activation, as measured by suppression of ISR-induced translational arrest and SG formation. N2b mutations that prevent dsRNA binding abrogate these activities also when introduced in the intact N protein. Substitutions reported to block post-translation modifications of N or its interaction with G3BP1/2 did not have a detectable additive effect. In an encephalomyocarditis virus-based infection model, N2b - but not a derivative defective in RNA binding-prevented PKR activation, inhibited β-interferon expression and promoted virus replication. Apparently, SARS-CoV-2 N inhibits innate immunity by sequestering dsRNA to prevent activation of PKR and RIG-I-like receptors. Similar observations were made for the N protein of human coronavirus 229E, suggesting that this may be a general trait conserved among members of other orthocoronavirus (sub)genera.

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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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