Format

Send to

Choose Destination
Cell Rep. 2014 Mar 27;6(6):1026-1036. doi: 10.1016/j.celrep.2014.02.027. Epub 2014 Mar 13.

Marburgvirus hijacks nrf2-dependent pathway by targeting nrf2-negative regulator keap1.

Author information

1
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.
2
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.
3
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA.
4
IMAP team, CIRI, Lyon 69007, France.
5
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
6
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.

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.

PMID:
24630992
DOI:
10.1016/j.celrep.2014.02.027
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center