Nuclear AGO2 supports influenza A virus replication through type-I interferon regulation.

IF 16.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nucleic Acids Research Pub Date : 2025-04-10 DOI:10.1093/nar/gkaf268

Hsiang-Chi Huang,Michelle Fong,Iwona Nowak,Evgeniia Shcherbinina,Vivian Lobo,Danica F Besavilla,Hang T Huynh,Karin Schön,Jakub O Westholm,Carola Fernandez,Angana A H Patel,Clotilde Wiel,Volkan I Sayin,Dimitrios G Anastasakis,Davide Angeletti,Aishe A Sarshad

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引用次数: 0

Abstract

The role of Argonaute (AGO) proteins and the RNA interference (RNAi) machinery in mammalian antiviral response has been debated. Therefore, we set out to investigate how mammalian RNAi impacts influenza A virus (IAV) infection. We reveal that IAV infection triggers nuclear accumulation of AGO2, which is directly facilitated by p53 activation. Mechanistically, we show that IAV induces nuclear AGO2 targeting of TRIM71and type-I interferon-pathway genes for silencing. Accordingly, Tp53-/- mice do not accumulate nuclear AGO2 and demonstrate decreased susceptibility to IAV infection. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. Furthermore, the FDA-approved drug, arsenic trioxide, prevents p53 nuclear translocation, increases interferon response and decreases viral replication in vitro and in a mouse model in vivo. Our data indicate that targeting the AGO2:p53-mediated silencing of innate immunity may offer a promising strategy to mitigate viral infections.

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关于Argonaute（AGO）蛋白和RNA干扰（RNAi）机制在哺乳动物抗病毒反应中的作用一直存在争议。因此，我们着手研究哺乳动物的 RNAi 如何影响甲型流感病毒（IAV）感染。我们发现，IAV 感染会引发 AGO2 的核积累，而 p53 的激活会直接促进 AGO2 的积累。从机理上讲，我们发现 IAV 会诱导核 AGO2 靶向 TRIM71 和 I 型干扰素通路基因进行沉默。因此，Tp53-/-小鼠不会积累核AGO2，并表现出对IAV感染的易感性降低。因此，RNAi 机制被病毒劫持，以逃避免疫系统并支持病毒复制。此外，美国食品及药物管理局批准的药物三氧化二砷能阻止 p53 核转位，增加干扰素反应，并在体外和小鼠体内模型中减少病毒复制。我们的数据表明，针对 AGO2:p53 介导的先天性免疫沉默，可能是一种很有前景的缓解病毒感染的策略。

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.