The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway
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,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714000771 |
| _version_ | 1819030303626231808 |
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| author | 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. Basler |
| author_facet | 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. Basler |
| author_sort | Megan R. Edwards |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T06:28:01Z |
| format | Article |
| id | doaj.art-64b11afeb80f476e9c2478737f329ba6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T06:28:01Z |
| publishDate | 2014-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-64b11afeb80f476e9c2478737f329ba62022-12-21T19:13:05ZengElsevierCell Reports2211-12472014-03-01661017102510.1016/j.celrep.2014.01.043The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response PathwayMegan R. Edwards0Britney Johnson1Chad E. Mire2Wei Xu3Reed S. Shabman4Lauren N. Speller5Daisy W. Leung6Thomas W. Geisbert7Gaya K. Amarasinghe8Christopher F. Basler9Department Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USAGalveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USADepartment Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USAGalveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USADepartment Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USAKelch-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.http://www.sciencedirect.com/science/article/pii/S2211124714000771 |
| spellingShingle | 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. Basler The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway Cell Reports |
| title | The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway |
| title_full | The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway |
| title_fullStr | The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway |
| title_full_unstemmed | The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway |
| title_short | The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway |
| title_sort | marburg virus vp24 protein interacts with keap1 to activate the cytoprotective antioxidant response pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714000771 |
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