The Ebola Virus Nucleoprotein Recruits the Host PP2A-B56 Phosphatase to Activate Transcriptional Support Activity of VP30

Mol Cell. 2018 Jan 4;69(1):136-145.e6. doi: 10.1016/j.molcel.2017.11.034. Epub 2017 Dec 28.

Abstract

Transcription of the Ebola virus genome depends on the viral transcription factor VP30 in its unphosphorylated form, but the underlying molecular mechanism of VP30 dephosphorylation is unknown. Here we show that the Ebola virus nucleoprotein (NP) recruits the host PP2A-B56 protein phosphatase through a B56-binding LxxIxE motif and that this motif is essential for VP30 dephosphorylation and viral transcription. The LxxIxE motif and the binding site of VP30 in NP are in close proximity, and both binding sites are required for the dephosphorylation of VP30. We generate a specific inhibitor of PP2A-B56 and show that it suppresses Ebola virus transcription and infection. This work dissects the molecular mechanism of VP30 dephosphorylation by PP2A-B56, and it pinpoints this phosphatase as a potential target for therapeutic intervention.

Keywords: B56; B’; Ebola virus; LxxIxE; NP; PP2A; VP30; filovirus; nucleoprotein; transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Ebolavirus / genetics
  • Ebolavirus / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Nucleoproteins
  • Phosphorylation
  • Protein Interaction Domains and Motifs / genetics
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Protein Phosphatase 2 / metabolism*
  • RNA, Viral / metabolism
  • Transcription Factors / genetics*
  • Transcription, Genetic / genetics*
  • Vero Cells
  • Viral Proteins / genetics*
  • Virus Replication / genetics*

Substances

  • Nucleoproteins
  • RNA, Viral
  • Transcription Factors
  • VP30 protein, ebola virus
  • Viral Proteins
  • PP2A-B56alpha protein, human
  • Protein Phosphatase 2