Page Audrey, Volchkova Valentina A, Reid Saint Patrick, Mateo Mathieu, Bagnaud-Baule Audrey, Nemirov Kirill, Shurtleff Amy C, Lawrence Philip, Reynard Oliver, Ottmann Michele, Lotteau Vincent, Biswal Shyam S, Thimmulappa Rajesh K, Bavari Sina, Volchkov Viktor E
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.
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.
Cell Rep. 2014 Mar 27;6(6):1026-1036. doi: 10.1016/j.celrep.2014.02.027. Epub 2014 Mar 13.
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.
马尔堡病毒（MARV）在人类中具有很高的致死率，可引发以大量病毒复制和炎症失调为特征的出血热。在此，我们证明MARV的VP24与核转录因子红细胞衍生2（Nrf2）的负调控因子kelch样ECH相关蛋白1（Keap1）结合。VP24与Keap1 Kelch结构域的结合使Nrf2从Keap1介导的抑制中释放出来，促进一系列参与细胞对氧化应激反应和炎症反应调节的细胞保护基因的持续激活。在MARV感染期间以及MARV VP24异位表达时，均证明了Nrf2依赖性基因的表达增加。我们还表明，与野生型动物的致死性感染相比，Nrf2缺陷小鼠能够控制MARV感染，这表明Nrf2对MARV感染至关重要。我们得出结论，VP24驱动的Nrf2依赖性途径的激活可能导致宿主抗病毒炎症反应失调，并且尽管有这些反应，它仍能确保MARV感染细胞的存活。
