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 (+3 others)
2014 Cell Reports  
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
more » ... ar 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 VP24driven 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.
doi:10.1016/j.celrep.2014.02.027 pmid:24630992 fatcat:yhlmknmpojatjchxhci5trkpcy