Characterization of a Toxoplasma Effector Uncovers an Alternative GSK3/β-catenin-regulatory Pathway of Inflammation

Elife. 2018 Oct 15;7:e39887. doi: 10.7554/eLife.39887.

Abstract

The intracellular parasite Toxoplasma gondii, hijacks evolutionarily conserved host processes by delivering effector proteins into the host cell that shift gene expression in a timely fashion. We identified a parasite dense granule protein as GRA18 that once released in the host cell cytoplasm forms versatile complexes with regulatory elements of the β-catenin destruction complex. By interacting with GSK3/PP2A-B56, GRA18 drives β-catenin up-regulation and the downstream effects on host cell gene expression. In the context of macrophages infection, GRA18 induces the expression of a specific set of genes commonly associated with an anti-inflammatory response that includes those encoding chemokines CCL17 and CCL22. Overall, this study adds another original strategy by which T. gondii tachyzoites reshuffle the host cell interactome through a GSK3/β-catenin axis to selectively reprogram immune gene expression.

Keywords: Toxoplasma gondii; effector proteins; host-pathogen interactions; human; infectious disease; microbiology; mouse; parasitology; toxoplasmosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chemokines / metabolism
  • Cytoplasm / metabolism
  • Female
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • Protein Binding
  • Protein Domains
  • Protein Transport
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism
  • RAW 264.7 Cells
  • Signal Transduction*
  • Toxoplasma / metabolism*
  • Transcription, Genetic
  • Transcriptome / genetics
  • beta Catenin / metabolism*

Substances

  • Chemokines
  • Protozoan Proteins
  • beta Catenin
  • Glycogen Synthase Kinase 3