A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets

Yadi Zhou; Yuan Liu; Shagun Gupta; Mauricio I. Paramo; Yuan Hou; Chengsheng Mao; Yuan Luo; Julius Judd; Shayne Wierbowski; Marta Bertolotti; Mriganka Nerkar; Lara Jehi; Nir Drayman; Vlad Nicolaescu; Haley Gula; Savaş Tay; Glenn Randall; Peihui Wang; John T. Lis; Cédric Feschotte; Serpil C. Erzurum; Feixiong Cheng; Haiyuan Yu

doi:10.1038/s41587-022-01474-0

A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets

Yadi Zhou, Yuan Liu, Shagun Gupta, Mauricio I. Paramo, Yuan Hou, Chengsheng Mao, Yuan Luo, Julius Judd, Shayne Wierbowski, Marta Bertolotti, Mriganka Nerkar, Lara Jehi, Nir Drayman, Vlad Nicolaescu, Haley Gula, Savaş Tay, Glenn Randall, Peihui Wang, John T. Lis, Cédric FeschotteSerpil C. Erzurum, Feixiong Cheng^*, Haiyuan Yu^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

103 Scopus citations

Abstract

Studying viral–host protein–protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2–human protein–protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human–virus interactions and provides hits for further research on COVID-19 therapeutics.

Original language	English (US)
Pages (from-to)	128-139
Number of pages	12
Journal	Nature biotechnology
Volume	41
Issue number	1
DOIs	https://doi.org/10.1038/s41587-022-01474-0
State	Published - Jan 2023

Funding

This work was primarily supported by National Institute on Aging (NIA) grants U01AG073323, R01AG076448 and R01AG066707 to F.C., and NIGMS grant R01GM124559 and Cornell Rapid Research Response to SARS-CoV-2 Seed Grant to H.Y. This work was supported in part by NIA grants 3R01AG066707-01S1, 3R01AG066707-02S1 and R56AG074001 to F.C., National Institute of General Medical Sciences (NIGMS) grants R01GM125639, R01GM130885 and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK115398 to H.Y. and NIGMS grant RM1GM139738 and National Human Genome Research Institute (NHGRI) grant UM1HG009393 to H.Y. and J.T.L. C.F. was supported by R35GM122550 and U01HG009391. Y. Luo. was supported in part by R01LM013337. J.J. was supported by F31HG010820. M.I.P. was supported in part by a Cornell University Center for Vertebrate Genomics Scholarship.

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Zhou, Y., Liu, Y., Gupta, S., Paramo, M. I., Hou, Y., Mao, C., Luo, Y., Judd, J., Wierbowski, S., Bertolotti, M., Nerkar, M., Jehi, L., Drayman, N., Nicolaescu, V., Gula, H., Tay, S., Randall, G., Wang, P., Lis, J. T., ... Yu, H. (2023). A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology, 41(1), 128-139. https://doi.org/10.1038/s41587-022-01474-0

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title = "A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets",

abstract = "Studying viral–host protein–protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2–human protein–protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human–virus interactions and provides hits for further research on COVID-19 therapeutics.",

author = "Yadi Zhou and Yuan Liu and Shagun Gupta and Paramo, \{Mauricio I.\} and Yuan Hou and Chengsheng Mao and Yuan Luo and Julius Judd and Shayne Wierbowski and Marta Bertolotti and Mriganka Nerkar and Lara Jehi and Nir Drayman and Vlad Nicolaescu and Haley Gula and Sava{\c s} Tay and Glenn Randall and Peihui Wang and Lis, \{John T.\} and C{\'e}dric Feschotte and Erzurum, \{Serpil C.\} and Feixiong Cheng and Haiyuan Yu",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jan,

doi = "10.1038/s41587-022-01474-0",

language = "English (US)",

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Zhou, Y, Liu, Y, Gupta, S, Paramo, MI, Hou, Y, Mao, C , Luo, Y, Judd, J, Wierbowski, S, Bertolotti, M, Nerkar, M, Jehi, L, Drayman, N, Nicolaescu, V, Gula, H, Tay, S, Randall, G, Wang, P, Lis, JT, Feschotte, C, Erzurum, SC, Cheng, F & Yu, H 2023, 'A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets', Nature biotechnology, vol. 41, no. 1, pp. 128-139. https://doi.org/10.1038/s41587-022-01474-0

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AU - Zhou, Yadi

AU - Liu, Yuan

AU - Gupta, Shagun

AU - Paramo, Mauricio I.

AU - Hou, Yuan

AU - Mao, Chengsheng

AU - Luo, Yuan

AU - Judd, Julius

AU - Wierbowski, Shayne

AU - Bertolotti, Marta

AU - Nerkar, Mriganka

AU - Jehi, Lara

AU - Drayman, Nir

AU - Nicolaescu, Vlad

AU - Gula, Haley

AU - Tay, Savaş

AU - Randall, Glenn

AU - Wang, Peihui

AU - Lis, John T.

AU - Feschotte, Cédric

AU - Erzurum, Serpil C.

AU - Cheng, Feixiong

AU - Yu, Haiyuan

PY - 2023/1

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N2 - Studying viral–host protein–protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2–human protein–protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human–virus interactions and provides hits for further research on COVID-19 therapeutics.

AB - Studying viral–host protein–protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2–human protein–protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human–virus interactions and provides hits for further research on COVID-19 therapeutics.

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A comprehensive SARS-CoV-2–human protein–protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets

Abstract

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ASJC Scopus subject areas

UN SDGs

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