Ubiquitination and Degradation of GBPs by a Shigella Effector to Suppress Host Defence

Nature. 2017 Nov 16;551(7680):378-383. doi: 10.1038/nature24467. Epub 2017 Oct 11.


Interferon-inducible guanylate-binding proteins (GBPs) mediate cell-autonomous antimicrobial defences. Shigella flexneri, a Gram-negative cytoplasmic free-living bacterium that causes bacillary dysentery, encodes a repertoire of highly similar type III secretion system effectors called invasion plasmid antigen Hs (IpaHs). IpaHs represent a large family of bacterial ubiquitin-ligases, but their function is poorly understood. Here we show that S. flexneri infection induces rapid proteasomal degradation of human guanylate binding protein-1 (hGBP1). We performed a transposon screen to identify a mutation in the S. flexneri gene ipaH9.8 that prevented hGBP1 degradation. IpaH9.8 targets hGBP1 for degradation via Lys48-linked ubiquitination. IpaH9.8 targets multiple GBPs in the cytoplasm independently of their nucleotide-bound states and their differential function in antibacterial defence, promoting S. flexneri replication and resulting in the death of infected mice. In the absence of IpaH9.8, or when binding of GBPs to IpaH9.8 was disrupted, GBPs such as hGBP1 and mouse GBP2 (mGBP2) translocated to intracellular S. flexneri and inhibited bacterial replication. Like wild-type mice, mutant mice deficient in GBP1-3, 5 and 7 succumbed to S. flexneri infection, but unlike wild-type mice, mice deficient in these GBPs were also susceptible to S. flexneri lacking ipaH9.8. The mode of IpaH9.8 action highlights the functional importance of GBPs in antibacterial defences. IpaH9.8 and S. flexneri provide a unique system for dissecting GBP-mediated immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / immunology
  • Bacterial Proteins / metabolism
  • Cytoplasm / metabolism
  • Female
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / immunology*
  • GTP-Binding Proteins / metabolism*
  • Gene Deletion
  • Guanosine Triphosphate / metabolism
  • HeLa Cells
  • Humans
  • Interferons / immunology
  • Macrophages / immunology
  • Macrophages / microbiology
  • Mice
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis*
  • Shigella flexneri / enzymology*
  • Shigella flexneri / growth & development
  • Shigella flexneri / immunology*
  • Shigella flexneri / pathogenicity
  • Type III Secretion Systems
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*
  • Virulence / genetics


  • Bacterial Proteins
  • GBP1 protein, human
  • Type III Secretion Systems
  • Guanosine Triphosphate
  • Interferons
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • GTP-Binding Proteins
  • Gbp2 protein, mouse