Host Cell Subversion by Toxoplasma GRA16, an Exported Dense Granule Protein That Targets the Host Cell Nucleus and Alters Gene Expression

Cell Host Microbe. 2013 Apr 17;13(4):489-500. doi: 10.1016/j.chom.2013.03.002.

Abstract

After invading host cells, Toxoplasma gondii multiplies within a parasitophorous vacuole (PV) that is maintained by parasite proteins secreted from organelles called dense granules. Most dense granule proteins remain within the PV, and few are known to access the host cell cytosol. We identify GRA16 as a dense granule protein that is exported through the PV membrane and reaches the host cell nucleus, where it positively modulates genes involved in cell-cycle progression and the p53 tumor suppressor pathway. GRA16 binds two host enzymes, the deubiquitinase HAUSP and PP2A phosphatase, which exert several functions, including regulation of p53 and the cell cycle. GRA16 alters p53 levels in a HAUSP-dependent manner and induces nuclear translocation of the PP2A holoenzyme. Additionally, certain GRA16-deficient strains exhibit attenuated virulence, indicating the importance of these host alterations in pathogenesis. Therefore, GRA16 represents a potentially emerging subfamily of exported dense granule proteins that modulate host function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • Cell Cycle / genetics
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / parasitology
  • Endopeptidases / genetics
  • Endopeptidases / metabolism
  • Female
  • Gene Expression
  • HEK293 Cells
  • Host-Parasite Interactions
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Sequence Alignment
  • Toxoplasma / genetics
  • Toxoplasma / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Virulence

Substances

  • Protozoan Proteins
  • Tumor Suppressor Protein p53
  • Endopeptidases