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.
authors.affiliation: Department Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Edwards
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Britney
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Galveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.
authors.forename: Reed S
authors.initials: RS
authors.lastname: Shabman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Speller
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daisy W
authors.initials: DW
authors.lastname: Leung
authors.affiliation: Galveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gaya K
authors.initials: GK
authors.lastname: Amarasinghe
authors.affiliation: Department Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA. Electronic address: chris.basler@mssm.edu.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D019610:Cytoprotection; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008379:Marburg Virus Disease / Q000378:metabolism / Q000821:virology; D029024:Marburgvirus / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014162:Transfection; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C094002:VP24 protein, Marburg virus; D014764:Viral Proteins