The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway

Megan R. Edwards, Britney Johnson, Chad Mire, Wei Xu, Reed S. Shabman, Lauren N. Speller, Daisy W. Leung, Thomas Geisbert, Gaya K. Amarasinghe, Christopher F. Basler

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1017-1025
Number of pages9
JournalCell Reports
Volume6
Issue number6
DOIs
StatePublished - Mar 27 2014

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Antioxidants
Marburgvirus
Antioxidant Response Elements
Ebolavirus
Proteins
Viruses
NF-E2 Transcription Factor
Democratic Republic of the Congo
Ubiquitin-Protein Ligases
Ubiquitination
Zoonoses
Infection
Kelch-Like ECH-Associated Protein 1
Marburg virus VP24 protein
Protein Binding
Pathogens
Transcription
Gene expression
Stoichiometry
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway. / Edwards, Megan R.; Johnson, Britney; Mire, Chad; Xu, Wei; Shabman, Reed S.; Speller, Lauren N.; Leung, Daisy W.; Geisbert, Thomas; Amarasinghe, Gaya K.; Basler, Christopher F.

In: Cell Reports, Vol. 6, No. 6, 27.03.2014, p. 1017-1025.

Research output: Contribution to journalArticle

Edwards, MR, Johnson, B, Mire, C, Xu, W, Shabman, RS, Speller, LN, Leung, DW, Geisbert, T, Amarasinghe, GK & Basler, CF 2014, 'The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway', Cell Reports, vol. 6, no. 6, pp. 1017-1025. https://doi.org/10.1016/j.celrep.2014.01.043
Edwards, Megan R. ; Johnson, Britney ; Mire, Chad ; Xu, Wei ; Shabman, Reed S. ; Speller, Lauren N. ; Leung, Daisy W. ; Geisbert, Thomas ; Amarasinghe, Gaya K. ; Basler, Christopher F. / The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway. In: Cell Reports. 2014 ; Vol. 6, No. 6. pp. 1017-1025.
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