Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1

Audrey Page; Valentina A. Volchkova; Saint Patrick Reid; Mathieu Mateo; Audrey Bagnaud-Baule; Kirill Nemirov; Amy C. Shurtleff; Philip Lawrence; Oliver Reynard; Michele Ottmann; Vincent Lotteau; Shyam S. Biswal; Rajesh K. Thimmulappa; Sina Bavari; Viktor E. Volchkov

doi:10.1016/j.celrep.2014.02.027

Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1

Audrey Page, Valentina A. Volchkova, Saint Patrick Reid, Mathieu Mateo, Audrey Bagnaud-Baule, Kirill Nemirov, Amy C. Shurtleff, Philip Lawrence, Oliver Reynard, Michele Ottmann, Vincent Lotteau, Shyam S. Biswal, Rajesh K. Thimmulappa, Sina Bavari, Viktor E. Volchkov

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

73 Scopus citations

Abstract

Marburg virus (MARV) has a high fatality rate in humans, causing hemorrhagic fever characterized by massive viral replication and dysregulated inflammation. Here, we demonstrate that VP24 of MARV bindsKelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear transcription factor erythroid-derived 2 (Nrf2). Binding of VP24 to Keap1 Kelch domain releases Nrf2 from Keap1-mediated inhibition promoting persistent activation of a panoply of cytoprotective genes implicated in cellular responses to oxidative stress and regulation of inflammatory responses. Increased expression of Nrf2-dependent genes was demonstrated both during MARV infection and upon ectopic expression of MARV VP24. We also show that Nrf2-deficient mice can control MARV infection when compared to lethal infection in wild-type animals, indicating that Nrf2 is critical for MARV infection. We conclude that VP24-driven activation of the Nrf2-dependent pathway is likely to contribute to dysregulation of host antiviral inflammatory responses and that it ensures survival of MARV-infected cells despite these responses.

Original language	English (US)
Pages (from-to)	1026-1036
Number of pages	11
Journal	Cell Reports
Volume	6
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2014.02.027
State	Published - Mar 27 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2014.02.027

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Page, A., Volchkova, V. A., Reid, S. P., Mateo, M., Bagnaud-Baule, A., Nemirov, K., Shurtleff, A. C., Lawrence, P., Reynard, O., Ottmann, M., Lotteau, V., Biswal, S. S., Thimmulappa, R. K., Bavari, S., & Volchkov, V. E. (2014). Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1. Cell Reports, 6(6), 1026-1036. https://doi.org/10.1016/j.celrep.2014.02.027

Page, A, Volchkova, VA, Reid, SP, Mateo, M, Bagnaud-Baule, A, Nemirov, K, Shurtleff, AC, Lawrence, P, Reynard, O, Ottmann, M, Lotteau, V, Biswal, SS, Thimmulappa, RK, Bavari, S & Volchkov, VE 2014, 'Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1', Cell Reports, vol. 6, no. 6, pp. 1026-1036. https://doi.org/10.1016/j.celrep.2014.02.027

@article{379e609852f54e2b80cd72219fe93f98,

title = "Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1",

abstract = "Marburg virus (MARV) has a high fatality rate in humans, causing hemorrhagic fever characterized by massive viral replication and dysregulated inflammation. Here, we demonstrate that VP24 of MARV bindsKelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear transcription factor erythroid-derived 2 (Nrf2). Binding of VP24 to Keap1 Kelch domain releases Nrf2 from Keap1-mediated inhibition promoting persistent activation of a panoply of cytoprotective genes implicated in cellular responses to oxidative stress and regulation of inflammatory responses. Increased expression of Nrf2-dependent genes was demonstrated both during MARV infection and upon ectopic expression of MARV VP24. We also show that Nrf2-deficient mice can control MARV infection when compared to lethal infection in wild-type animals, indicating that Nrf2 is critical for MARV infection. We conclude that VP24-driven activation of the Nrf2-dependent pathway is likely to contribute to dysregulation of host antiviral inflammatory responses and that it ensures survival of MARV-infected cells despite these responses.",

author = "Audrey Page and Volchkova, {Valentina A.} and Reid, {Saint Patrick} and Mathieu Mateo and Audrey Bagnaud-Baule and Kirill Nemirov and Shurtleff, {Amy C.} and Philip Lawrence and Oliver Reynard and Michele Ottmann and Vincent Lotteau and Biswal, {Shyam S.} and Thimmulappa, {Rajesh K.} and Sina Bavari and Volchkov, {Viktor E.}",

note = "Funding Information: We are grateful to A.I. Cederbaum (Mount Sinai School of Medicine, New York) for the pHCMV-Nrf2 and pHHO1-Luc reporter system and to M. Yamamoto for pmNQO1-ARE-Luc. We thank L. Tafforeau, M. Lebreton, and T. Chantier for technical help with double-hybrid screening and S. Naik for reading the manuscript. We would like to acknowledge the Biosafety team members of the Jean M{\'e}rieux BSL4 facility. This work was supported by the European Union FP7 project ANTIGONE (278976), Agence Nationale de la Recherche (ANR-07-MIME-006-01), and Fondation pour la Recherche M{\'e}dicale (DMI20091117323). ",

year = "2014",

month = mar,

day = "27",

doi = "10.1016/j.celrep.2014.02.027",

language = "English (US)",

volume = "6",

pages = "1026--1036",

journal = "Cell Reports",

issn = "2211-1247",

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number = "6",

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T1 - Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1

AU - Page, Audrey

AU - Volchkova, Valentina A.

AU - Reid, Saint Patrick

AU - Mateo, Mathieu

AU - Bagnaud-Baule, Audrey

AU - Nemirov, Kirill

AU - Shurtleff, Amy C.

AU - Lawrence, Philip

AU - Reynard, Oliver

AU - Ottmann, Michele

AU - Lotteau, Vincent

AU - Biswal, Shyam S.

AU - Thimmulappa, Rajesh K.

AU - Bavari, Sina

AU - Volchkov, Viktor E.

N1 - Funding Information: We are grateful to A.I. Cederbaum (Mount Sinai School of Medicine, New York) for the pHCMV-Nrf2 and pHHO1-Luc reporter system and to M. Yamamoto for pmNQO1-ARE-Luc. We thank L. Tafforeau, M. Lebreton, and T. Chantier for technical help with double-hybrid screening and S. Naik for reading the manuscript. We would like to acknowledge the Biosafety team members of the Jean Mérieux BSL4 facility. This work was supported by the European Union FP7 project ANTIGONE (278976), Agence Nationale de la Recherche (ANR-07-MIME-006-01), and Fondation pour la Recherche Médicale (DMI20091117323).

PY - 2014/3/27

Y1 - 2014/3/27

N2 - Marburg virus (MARV) has a high fatality rate in humans, causing hemorrhagic fever characterized by massive viral replication and dysregulated inflammation. Here, we demonstrate that VP24 of MARV bindsKelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear transcription factor erythroid-derived 2 (Nrf2). Binding of VP24 to Keap1 Kelch domain releases Nrf2 from Keap1-mediated inhibition promoting persistent activation of a panoply of cytoprotective genes implicated in cellular responses to oxidative stress and regulation of inflammatory responses. Increased expression of Nrf2-dependent genes was demonstrated both during MARV infection and upon ectopic expression of MARV VP24. We also show that Nrf2-deficient mice can control MARV infection when compared to lethal infection in wild-type animals, indicating that Nrf2 is critical for MARV infection. We conclude that VP24-driven activation of the Nrf2-dependent pathway is likely to contribute to dysregulation of host antiviral inflammatory responses and that it ensures survival of MARV-infected cells despite these responses.

AB - Marburg virus (MARV) has a high fatality rate in humans, causing hemorrhagic fever characterized by massive viral replication and dysregulated inflammation. Here, we demonstrate that VP24 of MARV bindsKelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear transcription factor erythroid-derived 2 (Nrf2). Binding of VP24 to Keap1 Kelch domain releases Nrf2 from Keap1-mediated inhibition promoting persistent activation of a panoply of cytoprotective genes implicated in cellular responses to oxidative stress and regulation of inflammatory responses. Increased expression of Nrf2-dependent genes was demonstrated both during MARV infection and upon ectopic expression of MARV VP24. We also show that Nrf2-deficient mice can control MARV infection when compared to lethal infection in wild-type animals, indicating that Nrf2 is critical for MARV infection. We conclude that VP24-driven activation of the Nrf2-dependent pathway is likely to contribute to dysregulation of host antiviral inflammatory responses and that it ensures survival of MARV-infected cells despite these responses.

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U2 - 10.1016/j.celrep.2014.02.027

DO - 10.1016/j.celrep.2014.02.027

M3 - Article

C2 - 24630992

AN - SCOPUS:84897095146

SN - 2211-1247

VL - 6

SP - 1026

EP - 1036

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1

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