The Toxoplasma pseudokinase ROP5 forms complexes with ROP18 and ROP17 kinases that synergize to control acute virulence in mice

Cell Host Microbe. 2014 May 14;15(5):537-50. doi: 10.1016/j.chom.2014.04.002.

Abstract

Polymorphic rhoptry-secreted kinases (ROPs) are essential virulence factors of Toxoplasma gondii. In particular, the pseudokinase ROP5 is the major determinant of acute virulence in mice, but the underlying mechanisms are unclear. We developed a tandem affinity protein tagging and purification approach in T. gondii and used it to show that ROP5 complexes with the active kinases ROP18 and ROP17. Biochemical analyses indicate that ROP18 and ROP17 have evolved to target adjacent and essential threonine residues in switch region I of immunity-related guanosine triphosphatases (GTPases) (IRGs), a family of host defense molecules that function to control intracellular pathogens. The combined activities of ROP17 and ROP18 contribute to avoidance of IRG recruitment to the intracellular T. gondii-containing vacuole, thus protecting the parasite from clearance in interferon-activated macrophages. These studies reveal an intricate, multilayered parasite survival strategy involving pseudokinases that regulate multiple active kinase complexes to synergistically thwart innate immunity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • GTP Phosphohydrolases / metabolism
  • Host-Parasite Interactions
  • Humans
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Sequence Alignment
  • Toxoplasma / chemistry
  • Toxoplasma / enzymology*
  • Toxoplasma / genetics
  • Toxoplasma / pathogenicity*
  • Toxoplasmosis / enzymology
  • Toxoplasmosis / parasitology*
  • Virulence
  • Virulence Factors / chemistry
  • Virulence Factors / genetics
  • Virulence Factors / metabolism*

Substances

  • Protozoan Proteins
  • Virulence Factors
  • Protein-Serine-Threonine Kinases
  • rhoptry protein 17, Toxoplasma gondii
  • GTP Phosphohydrolases