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Title: A Novel Secreted Protein, MYR1, Is Central to Toxoplasma ’s Manipulation of Host Cells

The intracellular protozoanToxoplasma gondiidramatically reprograms the transcriptome of host cells it infects, including substantially up-regulating the host oncogene c-myc. By applying a flow cytometry-based selection to infected mouse cells expressing green fluorescent protein fused to c-Myc (c-Myc–GFP), we isolated mutant tachyzoites defective in this host c-Myc up-regulation. Whole-genome sequencing of three such mutants led to the identification ofMYR1(Mycregulation1;TGGT1_254470) as essential for c-Myc induction. MYR1 is a secreted protein that requires TgASP5 to be cleaved into two stable portions, both of which are ultimately found within the parasitophorous vacuole and at the parasitophorous vacuole membrane. Deletion ofMYR1revealed that in addition to its requirement for c-Myc up-regulation, the MYR1 protein is needed for the ability ofToxoplasmatachyzoites to modulate several other important host pathways, including those mediated by the dense granule effectors GRA16 and GRA24. This result, combined with its location at the parasitophorous vacuole membrane, suggested that MYR1 might be a component of the machinery that translocatesToxoplasmaeffectors from the parasitophorous vacuole into the host cytosol. Support for this possibility was obtained by showing that transit of GRA24 to the host nucleus is indeed MYR1-dependent. As predicted by this pleiotropic phenotype, parasites deficient inMYR1were found to be severely attenuated in a mousemore » model of infection. We conclude, therefore, that MYR1 is a novel protein that plays a critical role in howToxoplasmadelivers effector proteins to the infected host cell and that this is crucial to virulence. IMPORTANCEToxoplasma gondiiis an important human pathogen and a model for the study of intracellular parasitism. Infection of the host cell withToxoplasmatachyzoites involves the introduction of protein effectors, including many that are initially secreted into the parasitophorous vacuole but must ultimately translocate to the host cell cytosol to function. The work reported here identified a novel protein that is required for this translocation. In conclusion, these results give new insight into a very unusual cell biology process as well as providing a potential handle on a pathway that is necessary for virulence and, therefore, a new potential target for chemotherapy.« less
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [2] ;  [2] ;  [4] ;  [4] ;  [3] ;  [2]
  1. Stanford Univ. School of Medicine, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. Stanford Univ. School of Medicine, CA (United States)
  3. Univ. of California, Santa Cruz, CA (United States)
  4. Washington Univ., St. Louis, MO (United States)
Publication Date:
OSTI Identifier:
1259517
Grant/Contract Number:
R21-AI112962; RO1-AI73756; T32-AI007328; P01-35HG000205; T32-AI007290; F31-AI120649; K08AI102946-01; S10RR025518-01; P30-NS069375
Type:
Accepted Manuscript
Journal Name:
mBio (Online)
Additional Journal Information:
Journal Name: mBio (Online); Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2150-7511
Publisher:
American Society for Microbiology
Research Org:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES