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

Jyoti Batra, Judd F. Hultquist, Dandan Liu, Olena Shtanko, John Von Dollen, Laura Satkamp, Gwendolyn M. Jang, Priya Luthra, Toni M. Schwarz, Gabriel I. Small, Eusondia Arnett, Manu Anantpadma, Ann Reyes, Daisy W. Leung, Robyn Kaake, Paige Haas, Carson B. Schmidt, Larry S. Schlesinger, Douglas J. LaCount, Robert A. DaveyGaya K. Amarasinghe, Christopher F. Basler*, Nevan J. Krogan

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

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. A host-Ebola protein-protein interaction map identifies candidate drug targets, including a host ubiquitin ligase that prevents viral replication, peptide mimics of which strongly inhibit Ebola replication in multiple cell types.

Original languageEnglish (US)
Pages (from-to)1917-1930.e13
JournalCell
Volume175
Issue number7
DOIs
StatePublished - Dec 13 2018

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Batra, J., Hultquist, J. F., Liu, D., Shtanko, O., Von Dollen, J., Satkamp, L., Jang, G. M., Luthra, P., Schwarz, T. M., Small, G. I., Arnett, E., Anantpadma, M., Reyes, A., Leung, D. W., Kaake, R., Haas, P., Schmidt, C. B., Schlesinger, L. S., LaCount, D. J., ... Krogan, N. J. (2018). Protein Interaction Mapping Identifies RBBP6 as a Negative Regulator of Ebola Virus Replication. Cell, 175(7), 1917-1930.e13. https://doi.org/10.1016/j.cell.2018.08.044