Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress of VP40 VLPs

Viruses. 2021 Feb 12;13(2):288. doi: 10.3390/v13020288.

Abstract

Filoviruses Ebola (EBOV) and Marburg (MARV) are devastating high-priority pathogens capable of causing explosive outbreaks with high human mortality rates. The matrix proteins of EBOV and MARV, as well as eVP40 and mVP40, respectively, are the key viral proteins that drive virus assembly and egress and can bud independently from cells in the form of virus-like particles (VLPs). The matrix proteins utilize proline-rich Late (L) domain motifs (e.g., PPxY) to hijack specific host proteins that contain WW domains, such as the HECT family E3 ligases, to facilitate the last step of virus-cell separation. We identified E3 ubiquitin ligase Smad Ubiquitin Regulatory Factor 2 (SMURF2) as a novel interactor with VP40 that positively regulates VP40 VLP release. Our results show that eVP40 and mVP40 interact with the three WW domains of SMURF2 via their PPxY motifs. We provide evidence that the eVP40-SMURF2 interaction is functional as the expression of SMURF2 positively regulates VLP egress, while siRNA knockdown of endogenous SMURF2 decreases VLP budding compared to controls. In sum, our identification of novel interactor SMURF2 adds to the growing list of identified host proteins that can regulate PPxY-mediated egress of VP40 VLPs. A more comprehensive understanding of the modular interplay between filovirus VP40 and host proteins may lead to the development of new therapies to combat these deadly infections.

Keywords: E3 ubiquitin ligase; Ebola; Marburg; PPxY motif; SMURF2; VLP budding; VP40; WW-domain; filovirus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Ebolavirus / chemistry
  • Ebolavirus / genetics
  • Ebolavirus / physiology*
  • Hemorrhagic Fever, Ebola / enzymology*
  • Hemorrhagic Fever, Ebola / genetics
  • Hemorrhagic Fever, Ebola / virology
  • Humans
  • Marburg Virus Disease / enzymology*
  • Marburg Virus Disease / genetics
  • Marburg Virus Disease / virology
  • Marburgvirus / chemistry
  • Marburgvirus / genetics
  • Marburgvirus / physiology*
  • Protein Binding
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*
  • Virion / genetics
  • Virion / physiology
  • Virus Assembly
  • Virus Release*

Substances

  • VP40 protein, virus
  • Viral Matrix Proteins
  • SMURF2 protein, human
  • Ubiquitin-Protein Ligases