The host E3-ubiquitin ligase TRIM6 ubiquitinates the Ebola virus VP35 protein and promotes virus replication

Preeti Bharaj, Colm Atkins, Priya Luthra, Maria Giraldo Giraldo, Brian E. Dawes, Lisa Miorin, Jeffrey R. Johnson, Nevan J. Krogan, Christopher F. Basler, Alexander Freiberg, Ricardo Rajsbaum Gorodezky

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21 Scopus citations

Abstract

Ebola virus (EBOV), a member of the Filoviridae family, is a highly pathogenic virus that causes severe hemorrhagic fever in humans and is responsible for epidemics throughout sub-Saharan, central, and West Africa. The EBOV genome encodes VP35, an important viral protein involved in virus replication by acting as an essential cofactor of the viral polymerase as well as a potent antagonist of the host antiviral type I interferon (IFN-I) system. By using mass spectrometry analysis and coimmunoprecipitation assays, we show here that VP35 is ubiquitinated on lysine 309 (K309), a residue located on its IFN antagonist domain. We also found that VP35 interacts with TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family. We recently reported that TRIM6 promotes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, to induce efficient antiviral IFN-I-mediated responses. Consistent with this notion, VP35 also associated noncovalently with polyubiquitin chains and inhibited TRIM6-mediated IFN-I induction. Intriguingly, we also found that TRIM6 enhances EBOV polymerase activity in a minigenome assay and TRIM6 knockout cells have reduced replication of infectious EBOV, suggesting that VP35 hijacks TRIM6 to promote EBOV replication through ubiquitination. Our work provides evidence that TRIM6 is an important host cellular factor that promotes EBOV replication, and future studies will focus on whether TRIM6 could be targeted for therapeutic intervention against EBOV infection.

Original languageEnglish (US)
Article numbere00833-17
JournalJournal of Virology
Volume91
Issue number18
DOIs
StatePublished - Sep 1 2017

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Keywords

  • Ebola virus
  • Innate immunity
  • TRIM6
  • Tripartite motif (TRIM) protein
  • Ubiquitination
  • Unanchored ubiquitin
  • Viral RNA polymerase
  • Virus-host interactions
  • VP35

ASJC Scopus subject areas

  • Immunology
  • Virology

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