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

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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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