Efficient invasion by Toxoplasma depends on the subversion of host protein networks
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Nature Publishing Group
Abstract
Apicomplexan parasites are important pathogens of humans and domestic animals, including Plasmodium species (the agents of malaria) and Toxoplasma gondii, which is responsible for toxoplasmosis. They replicate within the cells of their animal hosts, to which they gain access using a unique parasite-driven invasion process. At the core of the invasion machine is a structure at the interface between the invading parasite and host cell called the moving junction (MJ) 1 . The MJ serves as both a molecular doorway to the host cell and an anchor point enabling the parasite to engage its motility machinery to drive the penetration of the host cell 2, ultimately yielding a protective vacuole 3 . The MJ is established through self-assembly of parasite proteins at the parasite-host interface 4 . However, it is unknown whether host proteins are subverted for MJ formation. Here, we show that Toxoplasma parasite rhoptry neck proteins (RON2, RON4 and RON5) cooperate to actively recruit the host CIN85, CD2AP and the ESCRT-I components ALIX and TSG101 to the MJ during invasion. We map the interactions in detail and demonstrate that the parasite mimics and subverts conserved binding interfaces with remarkable specificity. Parasite mutants unable to recruit these host proteins show inefficient host cell invasion in culture and attenuated virulence in mice. This study reveals molecular mechanisms by which parasites subvert widely conserved host machinery to force highly efficient host cell access. © 2017 The Author(s).
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Adaptor proteins, signal transducing, Animals, Calcium-binding proteins, Cell cycle proteins, Cells, cultured, Cytoskeletal proteins, Disease models, animal, Dna-binding proteins, Endosomal sorting complexes required for transport, Female, Gene expression, Genetic vectors, Hela cells, Host-parasite interactions, Humans, Mice, Mice, inbred balb c, Organisms, genetically modified, Point mutation, Protozoan proteins, Recombinant proteins, Sf9 cells, Toxoplasma, Toxoplasmosis, Transcription factors, Apoptosis linked gene 2 interacting protein x, Cbl interacting protein of 85, Complementary dna, Crispr associated protein, Membrane protein, Rhoptry neck protein 2, Rhoptry neck protein 4, Rhoptry neck protein 5, Unclassified drug, Calcium binding protein, Cd2-associated protein, Cell cycle protein, Cytoskeleton protein, Dna binding protein, Escrt protein, Pdcd6ip protein, human, Protozoal protein, Recombinant protein, Rhoptry neck protein 2, toxoplasma gondii, Ron4 protein, toxoplasma gondii, Sh3kbp1 protein, human, Signal transducing adaptor protein, Transcription factor, Tumor susceptibility gene 101 protein, Animal experiment, Article, Binding site, Controlled study, Cytoskeleton, Fluorescence activated cell sorting, Homologous recombination, Host parasite interaction, Immunoprecipitation, Isothermal titration calorimetry, Molecular cloning, Molecular dynamics, Mouse, Nonhuman, Plasmid, Priority journal, Protein assembly, Protein binding, Protein localization, Protein motif, Protein protein interaction, Species conservation, Species invasion, Toxoplasma gondii, Animal, Bagg albino mouse, Cell culture, Disease model, Gene vector, Genetics, Hela cell line, Human, Metabolism, Pathogenicity, Physiology, Sf9 cell line, Transgenic organism