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

Franco, Magdalena; Panas, Michael W.; Marino, Nicole D.; Lee, Mei-Chong Wendy; Buchholz, Kerry R.; Kelly, Felice D.; Bednarski, Jeffrey J.; Sleckman, Barry P.; Pourmand, Nader; Boothroyd, John C.

doi:10.1128/mbio.02231-15

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

Journal Article · Mon Feb 01 23:00:00 EST 2016 · mBio (Online)

DOI:https://doi.org/10.1128/mbio.02231-15· OSTI ID:1259517

Franco, Magdalena ^[1]; Panas, Michael W. ^[2]; Marino, Nicole D. ^[2]; Lee, Mei-Chong Wendy ^[3]; Buchholz, Kerry R. ^[2]; Kelly, Felice D. ^[2]; Bednarski, Jeffrey J. ^[4]; Sleckman, Barry P. ^[4]; Pourmand, Nader ^[3]; Boothroyd, John C. ^[2]

Stanford Univ. School of Medicine, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Stanford Univ. School of Medicine, CA (United States)
Univ. of California, Santa Cruz, CA (United States)
Washington Univ., St. Louis, MO (United States)

The intracellular protozoan Toxoplasma gondii dramatically 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 of MYR1 (Myc regulation 1; 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 of MYR1 revealed that in addition to its requirement for c-Myc up-regulation, the MYR1 protein is needed for the ability of Toxoplasma tachyzoites 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 translocates Toxoplasma effectors 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 in MYR1 were found to be severely attenuated in a mouse model of infection. We conclude, therefore, that MYR1 is a novel protein that plays a critical role in how Toxoplasma delivers effector proteins to the infected host cell and that this is crucial to virulence.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

OSTI ID:: 1259517

Alternate ID(s):: OSTI ID: 1420295

Journal Information:: mBio (Online), Journal Name: mBio (Online) Journal Issue: 1 Vol. 7; ISSN 2150-7511

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Divergent kinase regulates membrane ultrastructure of the Toxoplasma parasitophorous vacuole Beraki, Tsebaot; Hu, Xiaoyu; Broncel, Malgorzata The Francis Crick Institute https://doi.org/10.25418/crick.11353610	text	January 2019
Divergent kinase regulates membrane ultrastructure of the Toxoplasma parasitophorous vacuole Beraki, Tsebaot; Hu, Xiaoyu; Broncel, Malgorzata The Francis Crick Institute https://doi.org/10.25418/crick.11353610.v1	text	January 2019
A CRISPR platform for targeted in vivo screens identifies Toxoplasma gondii virulence factors in mice. Young, Joanna; Dominicus, Caia; Wagener, Jeanette The Francis Crick Institute https://doi.org/10.25418/crick.11619474	text	January 2020
A CRISPR platform for targeted in vivo screens identifies Toxoplasma gondii virulence factors in mice. Young, Joanna; Dominicus, Caia; Wagener, Jeanette The Francis Crick Institute https://doi.org/10.25418/crick.11619474.v1	text	January 2020
Toxoplasma Does Not Secrete the GRA16 and GRA24 Effectors Beyond the Parasitophorous Vacuole Membrane of Tissue Cysts Krishnamurthy, Shruthi; Saeij, Jeroen P. J. Frontiers in Cellular and Infection Microbiology, Vol. 8 https://doi.org/10.3389/fcimb.2018.00366	journal	October 2018
Characterization of a Toxoplasma effector uncovers an alternative GSK3/β-catenin-regulatory pathway of inflammation He, Huan; Brenier-Pinchart, Marie-Pierre; Braun, Laurence eLife, Vol. 7 https://doi.org/10.7554/elife.39887	journal	October 2018