2. Academic Validation
  3. Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication

  • Cell. 2018 Dec 13;175(7):1917-1930.e13. doi: 10.1016/j.cell.2018.08.044.
Jyoti Batra 1,  Judd F Hultquist 2,  Dandan Liu 3,  Olena Shtanko 4,  John Von Dollen 5,  Laura Satkamp 5,  Gwendolyn M Jang 5,  Priya Luthra 6,  Toni M Schwarz 7,  Gabriel I Small 3,  Eusondia Arnett 8,  Manu Anantpadma 4,  Ann Reyes 4,  Daisy W Leung 3,  Robyn Kaake 5,  Paige Haas 5,  Carson B Schmidt 5,  Larry S Schlesinger 8,  Douglas J LaCount 9,  Robert A Davey 4,  Gaya K Amarasinghe 3,  Christopher F Basler 10,  Nevan J Krogan 11
Affiliations

Affiliations

  • 1 Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • 2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63105, USA.
  • 4 Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78245, USA.
  • 5 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • 6 Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
  • 7 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 8 Texas Biomedical Research Institute, San Antonio, TX 78245, USA.
  • 9 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
  • 10 Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. Electronic address: [email protected].
  • 11 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID: 30550789 DOI: 10.1016/j.cell.2018.08.044
Abstract

Ebola virus (EBOV) Infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during Infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. Domain mapping identified a 23 amino acid region within RBBP6 that binds to VP30. A crystal structure of the VP30-RBBP6 peptide complex revealed that RBBP6 mimics the viral nucleoprotein (NP) binding to the same interface of VP30. Knockdown of endogenous RBBP6 stimulated viral transcription and increased EBOV replication, whereas overexpression of either RBBP6 or the peptide strongly inhibited both. These results demonstrate the therapeutic potential of biologics that target this interface and identify additional PPIs that may be leveraged for novel therapeutic strategies.

Keywords

Ebola virus; RBBP6; RNA viruses; VP30; antiviral factor; host-pathogen interactions; protein-protein interactions; virus-host interactions.

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