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 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.
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Page
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Volchkova
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France; United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA.
authors.forename: Saint Patrick
authors.initials: SP
authors.lastname: Reid
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Mateo
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bagnaud-Baule
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Kirill
authors.initials: K
authors.lastname: Nemirov
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Shurtleff
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Philip
authors.initials: P
authors.lastname: Lawrence
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Reynard
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Ottmann
authors.affiliation: IMAP team, CIRI, Lyon 69007, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lotteau
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Biswal
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Thimmulappa
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.affiliation: Molecular Basis of Viral Pathogenicity, Centre International de Recherche en Infectologie (CIRI), INSERMU1111-CNRSUMR5308, Université de Lyon, Université Claude Bernard Lyon1, Ecole Normale Supérieure de Lyon, Lyon 69007, France. Electronic address: viktor.volchkov@inserm.fr.
authors.forename: Viktor E
authors.initials: VE
authors.lastname: Volchkov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D029024:Marburgvirus / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2