DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication

The SARS-CoV-2 pandemic and the emergence of novel variants underscore the need to understand host-virus interactions and identify host factors that restrict viral infection. Here, we perform a genome-wide CRISPR knockout screen to identify host restriction factors for SARS-CoV-2, revealing DAZAP2 as a potent antiviral gene. DAZAP2, previously implicated in SARS-CoV-2 restriction, is found to inhibit viral entry by blocking virion fusion with both endolysosomal and plasma membranes. Additionally, DAZAP2 suppresses genomic RNA replication without affecting the primary translation of viral replicases. We demonstrate that DAZAP2 functions as a pan-coronavirus restriction factor across four genera of coronaviruses. Importantly, knockout of <i>DAZAP2</i> enhances SARS-CoV-2 infection in mouse models and in human primary airway epithelial cells, confirming its physiological relevance. Mechanistically, the antiviral activity of DAZAP2 appears to be indirect, potentially through the regulation of host gene expression, as it primarily localizes to the nucleus. Our findings provide new insights into the host defense system against coronaviruses and highlight DAZAP2 as a potential target for host-directed antiviral therapies.IMPORTANCEDuring viral infection, the host defense response is mediated by a variety of host factors through distinct mechanisms that have yet to be fully elucidated. Although <i>DAZAP2</i> was previously implicated in SARS-CoV-2 restriction, its mechanisms of action and <i>in vivo</i> relevance remain unclear. In this study, we identify DAZAP2 as a potent pan-coronavirus restriction factor that inhibits viral infection through dual mechanisms: blocking virion fusion with both endolysosomal and plasma membranes, and suppressing genomic RNA replication. We confirm its physiological relevance in host defense using mouse models and primary cell cultures. This study advances our understanding of host-pathogen interactions. Targeting DAZAP2 or its regulatory pathways could provide a new approach to enhance host defense against current and future coronavirus threats.

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Publication Details

Journal
mBio
Published
2025-08-20
DOI
https://doi.org/10.1128/mbio.00385-25
Citations
1
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
1.40

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DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication

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article

DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication

Yu Yin, Jincun Zhao, Yuyan Wang, Lulu Yang, Ziqiao Wang, Lin Qiu, Xinxin Huang, Yingjie Sun, Yanlong Ma, Jiayu Wu, Zhichao Gao, Ying Liao, Jingxian Zhao, Yue Hong, Qiang Ding, Zhenghong Yuan, Ping Zhang, Rong Zhang, Qisheng Zhang, Youhua Xie, Chao Liu, Yanfeng Liu, Jing Sun, Jiannan Chen, Fei Feng, Rong Li, Yongheng Huang, Yunkai Zhu
article en
1 citations

Abstract

The SARS-CoV-2 pandemic and the emergence of novel variants underscore the need to understand host-virus interactions and identify host factors that restrict viral infection. Here, we perform a genome-wide CRISPR knockout screen to identify host restriction factors for SARS-CoV-2, revealing DAZAP2 as a potent antiviral gene. DAZAP2, previously implicated in SARS-CoV-2 restriction, is found to inhibit viral entry by blocking virion fusion with both endolysosomal and plasma membranes. Additionally, DAZAP2 suppresses genomic RNA replication without affecting the primary translation of viral replicases. We demonstrate that DAZAP2 functions as a pan-coronavirus restriction factor across four genera of coronaviruses. Importantly, knockout of <i>DAZAP2</i> enhances SARS-CoV-2 infection in mouse models and in human primary airway epithelial cells, confirming its physiological relevance. Mechanistically, the antiviral activity of DAZAP2 appears to be indirect, potentially through the regulation of host gene expression, as it primarily localizes to the nucleus. Our findings provide new insights into the host defense system against coronaviruses and highlight DAZAP2 as a potential target for host-directed antiviral therapies.IMPORTANCEDuring viral infection, the host defense response is mediated by a variety of host factors through distinct mechanisms that have yet to be fully elucidated. Although <i>DAZAP2</i> was previously implicated in SARS-CoV-2 restriction, its mechanisms of action and <i>in vivo</i> relevance remain unclear. In this study, we identify DAZAP2 as a potent pan-coronavirus restriction factor that inhibits viral infection through dual mechanisms: blocking virion fusion with both endolysosomal and plasma membranes, and suppressing genomic RNA replication. We confirm its physiological relevance in host defense using mouse models and primary cell cultures. This study advances our understanding of host-pathogen interactions. Targeting DAZAP2 or its regulatory pathways could provide a new approach to enhance host defense against current and future coronavirus threats.

mBioVol. 16(9)
Shanghai Medical College of Fudan University (CN), Sun Yat-sen University (CN), Hainan University (CN), Southern University of Science and Technology (CN), ShanghaiTech University (CN), Guangzhou Experimental Station (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Shanghai Veterinary Research Institute (CN), Cluster in Biomedicine (IT), Shanghai Customs College (CN), Institute for Biomedicine (IT), National Clinical Research (US), Applied Technologies (United States) (US), Center for High Pressure Science & Technology Advanced Research (CN), State Key Laboratory of Respiratory Disease (CN), Guangzhou Eighth People's Hospital (CN), Guangzhou Medical University (CN), Tsinghua University (CN)
Natural Science Foundation of Shanghai, National Natural Science Foundation of China, National Key Research and Development Program of China, Program of Shanghai Academic Research Leader
Openalex Percentile: Top 17%
SARS-CoV-2 and COVID-19 Research
1.40
DOIOpen Access PDFOpenAlex
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