SARS-CoV-2 NSP3/4 control formation of replication organelle and recruitment of RNA polymerase NSP12.

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2025-03-03 Epub Date: 2024-12-31 DOI:10.1083/jcb.202306101
Jinping Yang, Buyun Tian, Pei Wang, Rongrong Chen, Ke Xiao, Xubing Long, Xinyue Zheng, Yun Zhu, Fei Sun, Yongxia Shi, Yaming Jiu, Wei Ji, Yanhong Xue, Tao Xu, Zonghong Li
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Abstract

β-coronavirus rearranges the host cellular membranes to form double-membrane vesicles (DMVs) via NSP3/4, which anchor replication-transcription complexes (RTCs), thereby constituting the replication organelles (ROs). However, the impact of specific domains within NSP3/4 on DMV formation and RO assembly remains largely unknown. By using cryogenic-correlated light and electron microscopy (cryo-CLEM), we discovered that the N-terminal and C-terminal domains (NTD and CTD) of SARS-CoV-2 NSP3 are essential for DMV formation. Nevertheless, the CTD of NSP4 is not essential for DMV formation but regulates the DMV numbers. Additionally, the NTD of NSP3 is required for recruiting the RTC component to the cytosolic face of DMVs through direct interaction with NSP12 to assemble ROs. Furthermore, we observed that the size of NSP3/4-induced DMVs is smaller than virus-induced DMVs and established that RTC-mediated synthesis of double-stranded RNA (dsRNA) cargo plays a crucial role in determining DMV size. Collectively, our findings reveal that β-coronaviruses exploit the NSP3/4/12 axis to establish the viral ROs.

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SARS-CoV-2 NSP3/4控制复制细胞器的形成和RNA聚合酶NSP12的募集。
β-冠状病毒通过NSP3/4重组宿主细胞膜形成双膜囊泡(dmv),其锚定复制转录复合物(rtc),从而构成复制细胞器(ROs)。然而,NSP3/4中特定结构域对DMV形成和RO组装的影响在很大程度上仍然未知。通过低温相关光电子显微镜(cryo-CLEM),我们发现SARS-CoV-2 NSP3的n端和c端结构域(NTD和CTD)对DMV的形成至关重要。然而,NSP4的CTD对DMV的形成并不是必需的,而是调节DMV的数量。此外,NSP3的NTD通过与NSP12的直接相互作用来组装ROs,从而将RTC成分招募到dmv的细胞质表面。此外,我们观察到nsp3 /4诱导的DMV的大小比病毒诱导的DMV小,并确定rtc介导的双链RNA (dsRNA)货物的合成在DMV大小的决定中起关键作用。总的来说,我们的研究结果表明β-冠状病毒利用NSP3/4/12轴来建立病毒ROs。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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