Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

Ruochen Zang; James Brett Case; Eylan Yutuc; Xiucui Ma; Sheng Shen; Maria Florencia Gomez Castro; Zhuoming Liu; Qiru Zeng; Haiyan Zhao; Juhee Son; Paul W. Rothlauf; Alex J.B. Kreutzberger; Gaopeng Hou; Hu Zhang; Sayantan Bose; Xin Wang; Michael D. Vahey; Kartik Mani; William J. Griffiths; Tom Kirchhausen; Daved H. Fremont; Haitao Guo; Abhinav Diwan; Yuqin Wang; Michael S. Diamond; Sean P.J. Whelan; Siyuan Ding

doi:10.1073/pnas.2012197117

Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

Ruochen Zang, James Brett Case, Eylan Yutuc, Xiucui Ma, Sheng Shen, Maria Florencia Gomez Castro, Zhuoming Liu, Qiru Zeng, Haiyan Zhao, Juhee Son, Paul W. Rothlauf, Alex J.B. Kreutzberger, Gaopeng Hou, Hu Zhang, Sayantan Bose, Xin Wang, Michael D. Vahey, Kartik Mani, William J. Griffiths, Tom KirchhausenDaved H. Fremont, Haitao Guo, Abhinav Diwan, Yuqin Wang, Michael S. Diamond, Sean P.J. Whelan, Siyuan Ding

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177 Scopus citations

Abstract

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

Original language	English
Pages (from-to)	32105-32113
Number of pages	9
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	50
DOIs	https://doi.org/10.1073/pnas.2012197117
State	Published - Dec 15 2020

Keywords

COVID-19
Innate immunity
Interferon
SARS-CoV-2
Virus entry

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10.1073/pnas.2012197117

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Zang, R., Case, J. B., Yutuc, E., Ma, X., Shen, S., Castro, M. F. G., Liu, Z., Zeng, Q., Zhao, H., Son, J., Rothlauf, P. W., Kreutzberger, A. J. B., Hou, G., Zhang, H., Bose, S., Wang, X., Vahey, M. D., Mani, K., Griffiths, W. J., ... Ding, S. (2020). Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion. Proceedings of the National Academy of Sciences of the United States of America, 117(50), 32105-32113. https://doi.org/10.1073/pnas.2012197117

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title = "Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion",

abstract = "Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.",

keywords = "COVID-19, Innate immunity, Interferon, SARS-CoV-2, Virus entry",

author = "Ruochen Zang and Case, {James Brett} and Eylan Yutuc and Xiucui Ma and Sheng Shen and Castro, {Maria Florencia Gomez} and Zhuoming Liu and Qiru Zeng and Haiyan Zhao and Juhee Son and Rothlauf, {Paul W.} and Kreutzberger, {Alex J.B.} and Gaopeng Hou and Hu Zhang and Sayantan Bose and Xin Wang and Vahey, {Michael D.} and Kartik Mani and Griffiths, {William J.} and Tom Kirchhausen and Fremont, {Daved H.} and Haitao Guo and Abhinav Diwan and Yuqin Wang and Diamond, {Michael S.} and Whelan, {Sean P.J.} and Siyuan Ding",

year = "2020",

month = dec,

day = "15",

doi = "10.1073/pnas.2012197117",

language = "English",

volume = "117",

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Zang, R, Case, JB, Yutuc, E, Ma, X, Shen, S, Castro, MFG, Liu, Z, Zeng, Q, Zhao, H, Son, J, Rothlauf, PW, Kreutzberger, AJB, Hou, G, Zhang, H, Bose, S, Wang, X, Vahey, MD, Mani, K, Griffiths, WJ, Kirchhausen, T, Fremont, DH, Guo, H, Diwan, A, Wang, Y, Diamond, MS , Whelan, SPJ & Ding, S 2020, 'Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 50, pp. 32105-32113. https://doi.org/10.1073/pnas.2012197117

TY - JOUR

T1 - Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

AU - Zang, Ruochen

AU - Case, James Brett

AU - Yutuc, Eylan

AU - Ma, Xiucui

AU - Shen, Sheng

AU - Castro, Maria Florencia Gomez

AU - Liu, Zhuoming

AU - Zeng, Qiru

AU - Zhao, Haiyan

AU - Son, Juhee

AU - Rothlauf, Paul W.

AU - Kreutzberger, Alex J.B.

AU - Hou, Gaopeng

AU - Zhang, Hu

AU - Bose, Sayantan

AU - Wang, Xin

AU - Vahey, Michael D.

AU - Mani, Kartik

AU - Griffiths, William J.

AU - Kirchhausen, Tom

AU - Fremont, Daved H.

AU - Guo, Haitao

AU - Diwan, Abhinav

AU - Wang, Yuqin

AU - Diamond, Michael S.

AU - Whelan, Sean P.J.

AU - Ding, Siyuan

PY - 2020/12/15

Y1 - 2020/12/15

N2 - Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

AB - Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

KW - COVID-19

KW - Innate immunity

KW - Interferon

KW - SARS-CoV-2

KW - Virus entry

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U2 - 10.1073/pnas.2012197117

DO - 10.1073/pnas.2012197117

M3 - Article

C2 - 33239446

AN - SCOPUS:85097841356

SN - 0027-8424

VL - 117

SP - 32105

EP - 32113

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 50

ER -

Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

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Keywords

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