The SARS-CoV-2 nucleocapsid protein interferes with the full enzymatic activation of UPF1 and its interaction with UPF2

IF 16.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nucleic Acids Research Pub Date : 2025-01-20 DOI:10.1093/nar/gkaf010

Veronica Nuccetelli, Makram Mghezzi-Habellah, Séverine Deymier, Armelle Roisin, Francine Gérard-Baraggia, Cecilia Rocchi, Pierre-Damien Coureux, Patrice Gouet, Andrea Cimarelli, Vincent Mocquet, Francesca Fiorini

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引用次数: 0

Abstract

The nonsense-mediated mRNA decay (NMD) pathway triggers the degradation of defective mRNAs and governs the expression of mRNAs with specific characteristics. Current understanding indicates that NMD is often significantly suppressed during viral infections to protect the viral genome. In numerous viruses, this inhibition is achieved through direct or indirect interference with the RNA helicase UPF1, thereby promoting viral replication and enhancing pathogenesis. In this study, we employed biochemical, biophysical assays and cellular investigations to explore the interplay between UPF1 and the nucleocapsid (Np) protein of SARS-CoV-2. We evaluated their direct interaction and its impact on inhibiting cellular NMD. Furthermore, we characterized how this interaction affects UPF1’s enzymatic function. Our findings demonstrate that Np inhibits the unwinding activity of UPF1 by physically obstructing its access to structured nucleic acid substrates. Additionally, we showed that Np binds directly to UPF2, disrupting the formation of the UPF1/UPF2 complex essential for NMD progression. Intriguingly, our research also uncovered a surprising pro-viral role of UPF1 and an antiviral function of UPF2. These results unveil a novel, multi-faceted mechanism by which SARS-CoV-2 evades the host’s defenses and manipulates cellular components. This underscores the potential therapeutic strategy of targeting Np-UPF1/UPF2 interactions to treat COVID-19.

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SARS-CoV-2核衣壳蛋白干扰UPF1的全酶激活及其与UPF2的相互作用

无义介导的mRNA衰变（NMD）途径会触发缺陷mRNA的降解，并控制具有特定特征的mRNA的表达。目前的研究表明，在病毒感染期间，NMD 通常会受到严重抑制，以保护病毒基因组。在许多病毒中，这种抑制是通过直接或间接干扰 RNA 螺旋酶 UPF1 来实现的，从而促进病毒复制并增强致病机理。在本研究中，我们采用了生物化学、生物物理试验和细胞研究方法来探讨 UPF1 与 SARS-CoV-2 的核头皮（Np）蛋白之间的相互作用。我们评估了它们之间的直接相互作用及其对抑制细胞 NMD 的影响。此外，我们还描述了这种相互作用如何影响 UPF1 的酶功能。我们的研究结果表明，Np 通过物理方式阻碍 UPF1 进入结构化核酸底物，从而抑制了 UPF1 的解旋活性。此外，我们还发现，Np 直接与 UPF2 结合，破坏了对 NMD 进展至关重要的 UPF1/UPF2 复合物的形成。有趣的是，我们的研究还发现了 UPF1 令人惊讶的促病毒作用和 UPF2 的抗病毒功能。这些结果揭示了 SARS-CoV-2 逃避宿主防御和操纵细胞成分的新颖、多层面机制。这强调了针对 Np-UPF1/UPF2 相互作用治疗 COVID-19 的潜在治疗策略。

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

Nucleic Acids Research 生物-生化与分子生物学

CiteScore

27.10

自引率

4.70%

发文量

1057

审稿时长

2 months

期刊介绍： Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.