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 journalArticle

43 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1026-1036
Number of pages11
JournalCell Reports
Volume6
Issue number6
DOIs
StatePublished - Mar 27 2014

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Marburgvirus
Viruses
Virus Diseases
Genes
Chemical activation
Wild Animals
Oxidative stress
Antiviral Agents
Animals
Oxidative Stress
Fever
Transcription Factors
Inflammation
Survival

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Page, A., Volchkova, V. A., Reid, S. P., Mateo, M., Bagnaud-Baule, A., Nemirov, K., ... 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

Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1. / Page, Audrey; Volchkova, Valentina A.; Reid, Saint Patrick; Mateo, Mathieu; Bagnaud-Baule, Audrey; Nemirov, Kirill; Shurtleff, Amy C.; Lawrence, Philip; Reynard, Oliver; Ottmann, Michele; Lotteau, Vincent; Biswal, Shyam S.; Thimmulappa, Rajesh K.; Bavari, Sina; Volchkov, Viktor E.

In: Cell Reports, Vol. 6, No. 6, 27.03.2014, p. 1026-1036.

Research output: Contribution to journalArticle

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
Page, Audrey ; Volchkova, Valentina A. ; Reid, Saint Patrick ; Mateo, Mathieu ; Bagnaud-Baule, Audrey ; Nemirov, Kirill ; Shurtleff, Amy C. ; Lawrence, Philip ; Reynard, Oliver ; Ottmann, Michele ; Lotteau, Vincent ; Biswal, Shyam S. ; Thimmulappa, Rajesh K. ; Bavari, Sina ; Volchkov, Viktor E. / Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1. In: Cell Reports. 2014 ; Vol. 6, No. 6. pp. 1026-1036.
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