Global siRNA screen identifies human host factors critical for SARS-CoV-2 replication and late stages of infection

文献类型： 外文期刊

第一作者： Yin, Xin

作者： Yin, Xin;Pu, Yuan;De Jesus, Paul D.;Fuentes, Daniel;Mena, Ignacio;Chanda, Sumit K.;Yuan, Shuofeng;Pache, Lars;Churas, Christopher;Ideker, Trey;Pratt, Dexter;Weston, Stuart;Biddle, Grace;Doss-Gollin, Simon;Deming, Meagan;Frieman, Matthew B.;Riva, Laura;Chanda, Sumit K.;Simons, Lacy M.;Cisneros, William J.;Hultquist, Judd F.;Simons, Lacy M.;Cisneros, William J.;Hultquist, Judd F.;Clausen, Thomas;Esko, Jeffrey D.;Kim, Ha Na;Whitelock, John M.;Lord, Megan S.;Garcia-Sastre, Adolfo;Garcia-Sastre, Adolfo;Garcia-Sastre, Adolfo;Garcia-Sastre, Adolfo;Garcia-Sastre, Adolfo;Garcia-Sastre, Adolfo;Ideker, Trey;Martin-Sancho, Laura

作者机构：

期刊名称：PLOS BIOLOGY （ 影响因子：7.2； 五年影响因子：7.7 ）

ISSN： 1544-9173

年卷期： 2025 年 23 卷 6 期

页码：

收录情况： SCI

摘要： Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, most of these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased toward the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published functional screens and proteomics data to reveal (i) common pathways that were identified in all OMICs datasets-including regulation of Wnt signaling and gap junctions, (ii) pathways uniquely identified in this screen-including NADH oxidation, or (iii) pathways supported by this screen and proteomics data but not published functional screens-including arachionate production and MAPK signaling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 32 proteins that were determined to impact viral replication and 27 impacting late stages of infection, respectively. Additionally, a subset of proteins was tested across other coronaviruses revealing a subset of proviral factors that were conserved across pandemic SARS-CoV-2, epidemic SARS-CoV-1 and MERS-CoV, and the seasonal coronavirus OC43-CoV. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.

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