GBPs Inhibit Motility of Shigella Flexneri but Are Targeted for Degradation by the Bacterial Ubiquitin Ligase IpaH9.8

Cell Host Microbe. 2017 Oct 11;22(4):507-518.e5. doi: 10.1016/j.chom.2017.09.007.

Abstract

Interferon exposure boosts cell-autonomous immunity for more efficient pathogen control. But how interferon-enhanced immunity protects the cytosol against bacteria and how professionally cytosol-dwelling bacteria avoid clearance are insufficiently understood. Here we demonstrate that the interferon-induced GTPase family of guanylate-binding proteins (GBPs) coats Shigella flexneri in a hierarchical manner reliant on GBP1. GBPs inhibit actin-dependent motility and cell-to-cell spread of bacteria but are antagonized by IpaH9.8, a bacterial ubiquitin ligase secreted into the host cytosol. IpaH9.8 ubiquitylates GBP1, GBP2, and GBP4 to cause the proteasome-dependent destruction of existing GBP coats. This ubiquitin coating of Shigella favors the pathogen as it liberates bacteria from GBP encapsulation to resume actin-mediated motility and cell-to-cell spread. We conclude that an important function of GBP recruitment to S. flexneri is to prevent the spread of infection to neighboring cells while IpaH9.8 helps bacterial propagation by counteracting GBP-dependent cell-autonomous immunity.

Keywords: E3 ubiquitin ligase; GBP; Ipa9.8; cell-autonomous immunity; effector proteins; host-pathogen interaction; innate immunity; ubiquitin; ubiquitin coat.

MeSH terms

  • Antigens, Bacterial / chemistry
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism*
  • Cytosol / immunology*
  • Cytosol / microbiology
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / immunology
  • GTP-Binding Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Cellular
  • Immunity, Innate
  • Interferons / immunology
  • Interferons / metabolism
  • Proteolysis
  • Shigella flexneri / genetics
  • Shigella flexneri / immunology
  • Shigella flexneri / pathogenicity*
  • THP-1 Cells
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Interferons
  • Ubiquitin-Protein Ligases
  • GTP-Binding Proteins