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FXR 蛋白的液液相分离驱动复制细胞器聚集，从而促进 β 冠状病毒增殖。

LLPS of FXR proteins drives replication organelle clustering for β-coronaviral proliferation.

机构信息

Shenzhen Key Laboratory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology , Shenzhen, P.R. China.

Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, P.R. China.

出版信息

J Cell Biol. 2024 Jun 3;223(6). doi: 10.1083/jcb.202309140. Epub 2024 Apr 8.

DOI:10.1083/jcb.202309140
PMID:38587486
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11001562/
Abstract

β-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal that host fragile X-related (FXR) family proteins (FXR1/FXR2/FMR1) are required for DMV clustering induced by expression of viral non-structural proteins (Nsps) Nsp3 and Nsp4. Depleting FXRs results in DMV dispersion in the cytoplasm. FXR1/2 and FMR1 are recruited to DMV sites via specific interaction with Nsp3. FXRs form condensates driven by liquid-liquid phase separation, which is required for DMV clustering. FXR1 liquid droplets concentrate Nsp3 and Nsp3-decorated liposomes in vitro. FXR droplets facilitate recruitment of translation machinery for efficient translation surrounding DMVs. In cells depleted of FXRs, SARS-CoV-2 replication is significantly attenuated. Thus, SARS-CoV-2 exploits host FXR proteins to cluster viral DMVs via phase separation for efficient viral replication.

摘要

β 冠状病毒重塑宿主内膜系统，形成双层膜囊泡（DMVs）作为复制细胞器（ROs），为感染细胞中病毒 RNA 的合成提供了一个屏蔽的微环境。DMVs 是聚集的，但分子基础和病理生理功能仍然未知。在这里，我们揭示了宿主脆性 X 相关（FXR）家族蛋白（FXR1/FXR2/FMR1）是病毒非结构蛋白（Nsps）Nsp3 和 Nsp4 表达诱导的 DMV 聚集所必需的。耗尽 FXRs 会导致 DMV 在细胞质中分散。FXR1/2 和 FMR1 通过与 Nsp3 的特异性相互作用被募集到 DMV 位点。FXR 形成由液-液相分离驱动的凝聚体，这是 DMV 聚集所必需的。FXR1 液滴浓缩 Nsp3 和 Nsp3 修饰的脂质体在体外。FXR 液滴促进周围 DMVs 翻译机制的募集，以实现有效的翻译。在耗尽 FXR 的细胞中，SARS-CoV-2 的复制明显减弱。因此，SARS-CoV-2 通过相分离利用宿主 FXR 蛋白来聚集病毒 DMVs，从而实现高效的病毒复制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e139e0295426/JCB_202309140_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/a5343f629c75/JCB_202309140_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e08e0bfc56c0/JCB_202309140_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/a0a6a7b19595/JCB_202309140_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/1b2b43199afd/JCB_202309140_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/d33451a674b6/JCB_202309140_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e09d771a76a4/JCB_202309140_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/643f346b3cc9/JCB_202309140_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/6807aebf534c/JCB_202309140_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/a7f25b197f3b/JCB_202309140_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/8791141e5642/JCB_202309140_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/5b112848cb13/JCB_202309140_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e139e0295426/JCB_202309140_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/a5343f629c75/JCB_202309140_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e08e0bfc56c0/JCB_202309140_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/a0a6a7b19595/JCB_202309140_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/1b2b43199afd/JCB_202309140_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/d33451a674b6/JCB_202309140_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e09d771a76a4/JCB_202309140_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/643f346b3cc9/JCB_202309140_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/6807aebf534c/JCB_202309140_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/a7f25b197f3b/JCB_202309140_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/8791141e5642/JCB_202309140_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/5b112848cb13/JCB_202309140_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/096f/11001562/e139e0295426/JCB_202309140_Fig7.jpg

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