@article{d7c15bc633e9413aaf0cd7f850f6d76d,
title = "The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway",
abstract = "Kelch-like ECH-associated protein 1 (Keap1) is a ubiquitin E3 ligase specificity factor that targets transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) for ubiquitination and degradation. Disrupting Keap1-Nrf2 interaction stabilizes Nrf2, resulting in Nrf2 nuclear accumulation, binding to antioxidant response elements (AREs), and transcription of cytoprotective genes. Marburg virus (MARV) is a zoonotic pathogen that likely uses bats as reservoir hosts. We demonstrate that MARV protein VP24 (mVP24) binds the Kelch domain of either human or bat Keap1. This binding is of high affinity and 1:1 stoichiometry and activates Nrf2. Modeling based on the Zaire ebolavirus (EBOV) VP24 (eVP24) structure identified in mVP24 an acidic loop (K-loop) critical for Keap1 interaction. Transfer of the K-loop to eVP24, which otherwise does not bind Keap1, confers Keap1 binding and Nrf2 activation, and infection by MARV, but not EBOV, activates ARE gene expression. Therefore, MARV targets Keap1 to activate Nrf2-induced cytoprotective responses during infection.",
author = "Edwards, {Megan R.} and Britney Johnson and Mire, {Chad E.} and Wei Xu and Shabman, {Reed S.} and Speller, {Lauren N.} and Leung, {Daisy W.} and Geisbert, {Thomas W.} and Amarasinghe, {Gaya K.} and Basler, {Christopher F.}",
note = "Funding Information: This work was supported by NIH grants AI059536 (to C.F.B.) and AI081914 (to G.K.A.), DTRA grant HDTRA1-12-1-0051 (to C.F.B. and G.K.A.), and NSF graduate fellowship DGE-1143954 (to B.J.). All microscopy studies were performed with the generous assistance of the Icahn School of Medicine at Mount Sinai Microscopy Shared Resource Facility. Sequencing was performed at the Genomics Sequencing Facility at Mount Sinai. We thank Hardik Shah and the Bioinformatics Group of the Icahn Institute for Genomics and MultiScale Biology for help with sequence analysis. We thank Drs. S. Ginell, N. Duke, and J. Lazarz at the Structural Biology Center (Advanced Photon Source) and Dr. J. Nix at Beamline 4.2.2 (Advanced Light Source) for data collection support. Use of Argonne National Laboratory SBC beamlines at APS was supported by the U.S. D.O.E. contract DE-AC02-06CH11357. ",
year = "2014",
month = mar,
day = "27",
doi = "10.1016/j.celrep.2014.01.043",
language = "English",
volume = "6",
pages = "1017--1025",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}