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Virulence without catalysis: how can a pseudokinase affect host cell signaling?

Michael L Reese1, Jon P Boyle

  • 1Stanford University, Department of Microbiology and Immunology, 299 Campus Drive, Stanford, CA 94305-5124, USA. mlreese@stanford.edu

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Toxoplasma gondii secretes catalytically inactive protein kinases, called pseudokinases, to manipulate host cells. These pseudokinases, abundant in Toxoplasma, likely play a key role in parasitic infections by altering host signaling pathways.

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Area of Science:

  • Parasitology
  • Molecular Biology
  • Host-Pathogen Interactions

Background:

  • Pathogenic organisms secrete effectors to disrupt host cell functions and signaling.
  • The intracellular parasite Toxoplasma gondii possesses a unique virulence locus encoding catalytically inactive protein kinases (pseudokinases).
  • Toxoplasma gondii exhibits a high proportion of pseudokinases within its kinome, with many secreted into the host cell.

Purpose of the Study:

  • To investigate the role of pseudokinases in the virulence of Toxoplasma gondii.
  • To explore the potential of the pseudokinase fold for functional diversification in parasitic organisms.
  • To discuss the significance of gene expansion in pseudokinase loci and their impact on host signaling.

Main Methods:

  • Bioinformatic analysis of the Toxoplasma gondii kinome to identify and characterize pseudokinases.
  • Investigation of pseudokinase secretion pathways into host cells.
  • Comparative genomics to assess gene expansion at pseudokinase loci.

Main Results:

  • Identified a potent virulence locus in Toxoplasma gondii encoding a family of pseudokinases.
  • Confirmed that a significant number of Toxoplasma pseudokinases are secreted into the host cell.
  • Highlighted the high prevalence of pseudokinases in the Toxoplasma kinome compared to other organisms.

Conclusions:

  • The pseudokinase domain is a versatile scaffold potentially exploited for functional diversification in pathogens.
  • Gene expansion at pseudokinase loci may contribute to the evolution of parasitic virulence.
  • Secreted Toxoplasma pseudokinases likely employ novel mechanisms to modulate host cell signaling pathways.