SARS-CoV-2 NSP16 promotes IL-6 production by regulating the stabilization of HIF-1α

IF 4.4 2区 生物学 Q2 CELL BIOLOGY
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引用次数: 0

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19). Severe and fatal COVID-19 cases often display cytokine storm i.e. significant elevation of pro-inflammatory cytokines and acute respiratory distress syndrome (ARDS) with systemic hypoxia. Understanding the mechanisms of these pathogenic manifestations would be essential for the prevention and especially treatment of COVID-19 patients. Here, using a dual luciferase reporter assay for hypoxia-response element (HRE), we initially identified SARS-CoV-2 nonstructural protein 5 (NSP5), NSP16, and open reading frame 3a (ORF3a) to upregulate hypoxia-inducible factor-1α (HIF-1α) signaling. Further experiments showed NSP16 to have the most prominent effect on HIF-1α, thus contributing to the induction of COVID-19 associated pro-inflammatory response. We demonstrate that NSP16 interrupts von Hippel-Lindau (VHL) protein interaction with HIF-1α, thereby inhibiting ubiquitin-dependent degradation of HIF-1α and allowing it to bind HRE region in the IL-6 promoter region. Taken together, the findings imply that SARS-CoV-2 NSP16 induces HIF-1α expression, which in turn exacerbates the production of IL-6.

SARS-CoV-2 NSP16 通过调节 HIF-1α 的稳定促进 IL-6 的产生
严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)是冠状病毒病 2019(COVID-19)的病原体。严重和致命的 COVID-19 病例通常会表现出细胞因子风暴,即促炎症细胞因子显著升高和伴有全身缺氧的急性呼吸窘迫综合征(ARDS)。了解这些致病表现的机制对于预防和治疗 COVID-19 患者至关重要。在这里,我们利用低氧反应元件(HRE)的双荧光素酶报告分析法,初步确定了 SARS-CoV-2 非结构蛋白 5(NSP5)、NSP16 和开放阅读框 3a(ORF3a)可上调低氧诱导因子-1α(HIF-1α)信号传导。进一步的实验表明,NSP16 对 HIF-1α 的影响最为显著,因此有助于诱导与 COVID-19 相关的促炎反应。我们证明,NSP16 能中断 von Hippel-Lindau (VHL) 蛋白与 HIF-1α 的相互作用,从而抑制 HIF-1α 的泛素依赖性降解,使其能与 IL-6 启动子区的 HRE 区域结合。综上所述,这些研究结果表明,SARS-CoV-2 NSP16 可诱导 HIF-1α 的表达,进而加剧 IL-6 的产生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cellular signalling
Cellular signalling 生物-细胞生物学
CiteScore
8.40
自引率
0.00%
发文量
250
审稿时长
27 days
期刊介绍: Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.
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