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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 binds Kelch-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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Contributor : Laurence Naiglin Connect in order to contact the contributor
Submitted on : Tuesday, June 24, 2014 - 3:51:19 PM
Last modification on : Saturday, September 24, 2022 - 3:10:05 PM

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Audrey Page, Valentina A Volchkova, Saint Patrick Reid, Mathieu Mateo, Audrey Bagnaud-Baule, et al.. Marburgvirus hijacks nrf2-dependent pathway by targeting nrf2-negative regulator keap1.. Cell Reports, Elsevier Inc, 2014, 6 (6), pp.1026-36. ⟨10.1016/j.celrep.2014.02.027⟩. ⟨hal-01011795⟩



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