hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis

Cell Rep. 2020 May 19;31(7):107667. doi: 10.1016/j.celrep.2020.107667.


Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of GTPases and conveys host defense against intracellular bacteria and parasites. During infection, hGBP1 is recruited to pathogen-containing vacuoles, such as Chlamydia trachomatis inclusions, restricts pathogenic growth, and induces the activation of the inflammasome pathway. hGBP1 has a unique catalytic activity to hydrolyze guanosine triphosphate (GTP) to guanosine monophosphate (GMP) in two consecutive cleavage steps. However, the functional significance of this activity in host defense remains elusive. Here, we generate a structure-guided mutant that specifically abrogates GMP production, while maintaining fast cooperative GTP hydrolysis. Complementation experiments in human monocytes/macrophages show that hGBP1-mediated GMP production is dispensable for restricting Chlamydia trachomatis growth but is necessary for inflammasome activation. Mechanistically, GMP is catabolized to uric acid, which in turn activates the NLRP3 inflammasome. Our study demonstrates that the unique enzymology of hGBP1 coordinates bacterial growth restriction and inflammasome signaling.

Keywords: cell-autonomous immunity; dynamin GTPases; guanylate binding proteins; intracellular pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chlamydia Infections / immunology*
  • Chlamydia Infections / metabolism
  • Chlamydia Infections / microbiology
  • Chlamydia trachomatis / growth & development*
  • Cyclic GMP
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / immunology
  • GTP-Binding Proteins / metabolism*
  • Guanine Nucleotides / metabolism
  • Guanosine Triphosphate / metabolism*
  • Humans
  • Hydrolysis
  • Inflammasomes / immunology
  • Inflammasomes / metabolism*
  • Macrophages / immunology
  • Macrophages / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Signal Transduction
  • THP-1 Cells
  • Uric Acid / metabolism


  • GBP1 protein, human
  • Guanine Nucleotides
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Uric Acid
  • Guanosine Triphosphate
  • GTP-Binding Proteins
  • Cyclic GMP