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

• DOI: 10.1016/j.celrep.2014.01.043
• Publication Date: 2014-03-17T07:49:04Z
• Authors: Megan R. Edwards; Britney Johnson; Chad E. Mire; Wei Xu; Reed S. Shabman; Lauren N. Speller; Daisy W. Leung; Thomas W. Geisbert; Gaya K. Amarasinghe; Christopher F. Ba...
• Keywords: KEAP1; Marburg virus; Ebolavirus; NEDD4; VP40

Kelch-like ECH-associated protein 1 (Keap1) is a ubiquitin E3 ligase specificity factor that targets transcription nuclear (erythroid-derived 2)-like 2 (Nrf2) for ubiquitination and degradation. Disrupting Keap1-Nrf2 interaction stabilizes Nrf2, resulting in Nrf2 accumulation, binding to antioxidant response elements (AREs), of cytoprotective genes. Marburg virus (MARV) zoonotic pathogen likely uses bats as reservoir hosts. We demonstrate MARV VP24 (mVP24) binds the Kelch domain either human or bat Keap1. This high affinity 1:1 stoichiometry activates Nrf2. Modeling based on Zaire ebolavirus (EBOV) (eVP24) structure identified mVP24 an acidic loop (K-loop) critical Keap1 interaction. Transfer K-loop eVP24, which otherwise does not bind Keap1, confers activation, infection by MARV, but EBOV, ARE gene expression. Therefore, activate Nrf2-induced responses during infection.