MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to
            <i>Toxoplasma</i>
            , Including Counteracting MYR1-Independent Effects

Naor, Adit; Panas, Michael W.; Marino, Nicole D.; Coffey, Michael; Tonkin, Christopher J.; Boothroyd, John C.

doi:10.1128/mbio.02401-17

Cited by 57 publications

(71 citation statements)

References 40 publications

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“…Several publications have described the active interference of Toxoplasma tachyzoites with host cell cycle machinery (1, 2, 27, 28), including in MYR1-dependent ways (12). The results presented here for HCE1 likely provide at least a partial explanation for these effects since among the E2F-regulated genes whose expression is HCE1-dependent, we see several genes related to the pre-replication complex such as the minichromosome maintenance genes (MCM), DNA polymerase E and Origin Replication complex subunit 1 (ORC1).…”

Section: Discussionmentioning

confidence: 99%

“…The data showed the expected impacts on host processes already known to be caused by GRA16, GRA24, GRA18, and TgIST. They also showed, however, a profound and unexplained MYR1-dependent impact on gene sets defined as E2F targets and/or G2/M checkpoint control (12). The E2F transcription factors are a family of DNA binding proteins that form a heterodimer with Dimerization Partner 1 (DP1) and regulate a cohort of genes including cyclin E and its cyclin dependent kinase (CDK2) which control progression of the cell cycle (13).…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasmacontrols host cyclin E expression through the use of a novel MYR1-dependent effector protein, HCE1

Panas

Naor

Cygan

et al. 2019

Preprint

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toxoplasmacontrols host cyclin E expression through the use of a novel MYR1-dependent effector protein, HCE1

Panas

Naor

Cygan

et al. 2019

Preprint

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“…After invasion, Toxoplasma resides within the host cytosol in a PV and starts secreting GRAs into the PV lumen where they stay or get transported to the PVM or beyond the PVM into the host cell (Hakimi et al, 2017). The transport of GRAs beyond the PVM, but not onto the PVM, is mediated by a putative translocon containing the proteins MYR1/2/3 (Franco et al, 2016;Naor et al, 2018). However, Pru and PruΔmyr1 parasites showed similar IFNγ-mediated reductions in plaque number and area (Suppl.…”

Section: The Polymorphic Effector Gra15 Enhances Toxoplasma Susceptibmentioning

confidence: 99%

ToxoplasmaGRA15 limits parasite growth in IFNγ-activated fibroblasts through TRAF ubiquitin ligases

Mukhopadhyay

Sangaré

Braun

et al. 2020

Preprint

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The protozoan parasite Toxoplasma gondii lives inside a vacuole in the host cytoplasm where it is protected from host cytoplasmic innate immune responses. However, IFNγ-dependent cell-autonomous immunity can destroy the vacuole and the parasite inside. Toxoplasma strain differences in susceptibility to human IFNγ exist but the Toxoplasma effector(s) that determine these differences are unknown. We show that in human primary fibroblasts, the polymorphic Toxoplasma secreted effector GRA15 mediates the recruitment of ubiquitin ligases, including TRAF2 and TRAF6, to the vacuole membrane, which enhances recruitment of ubiquitin receptors (p62/NDP52) and ubiquitin-like molecules (LC3B, GABARAP). This ultimately leads to lysosomal degradation of the vacuole. In murine fibroblasts, GRA15-mediated TRAF6 recruitment mediates the recruitment of immunity-related GTPases and destruction of the vacuole. Thus, we have identified how the Toxoplasma effector GRA15 affects cell-autonomous immunity in human and murine cells.

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“…In contrast, MDGs have been detected by immunofluorescence assays in the nuclei of parasitized host cells at ∼3 hours post-invasion at the earliest (19), which suggests that they likely modulate host transcription much later than ROPs. Parasite mutants that lack a functional MYR complex have helped separate the impact of MDGs from those of other parasite effectors (25, 26, 31), but the specific impact on host transcription by ROPs and MIGs has yet to be determined. The rhoptry organelle’s contribution is of particular interest given that ROP injection is essential to parasite invasion, survival, and virulence, and the functions of most ROPs are unknown.…”

Section: Introductionmentioning

confidence: 99%

Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular ParasiteToxoplasma gondii

Rastogi

Xue

Quake

et al. 2020

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words 16Importance: 36 words ABSTRACT 30The intracellular parasite Toxoplasma gondii employs a vast array of effector 31 proteins from the rhoptry and dense granule organelles to modulate host cell biology; 32 these effectors are known as ROPs and GRAs, respectively. To examine the individual 33 impacts of ROPs and GRAs on host gene expression, we developed a robust, novel 34 protocol to enrich for ultra-pure populations of a naturally occurring and reproducible 35 population of host cells called uninfected-injected (U-I) cells, which Toxoplasma injects 36with ROPs but subsequently fails to invade. We then performed single cell 37 transcriptomic analysis at 1-3 hours post-infection on U-I cells (as well as on uninfected 38 and infected controls) arising from infection with either wild type parasites or parasites 39 lacking the MYR1 protein, which is required for soluble GRAs to cross the 40 parasitophorous vacuole membrane (PVM) and reach the host cell cytosol. Based on 41 comparisons of infected and U-I cells, the host's earliest response to infection appears 42 to be driven primarily by the injected ROPs, which appear to induce immune and 43 cellular stress pathways. These ROP-dependent pro-inflammatory signatures appear to 44 be counteracted by at least some of the MYR1-dependent GRAs and may be enhanced 45 by the MYR-independent GRAs, (which are found embedded within the PVM). Finally, 46 signatures detected in uninfected bystander cells from the infected monolayers 47 suggests that MYR1-dependent paracrine effects also counteract inflammatory ROP-48 dependent processes. 49 50 IMPORTANCE 51 This work performs the first transcriptomic analysis of U-I cells, captures the 52 earliest stage of a host cell's interaction with Toxoplasma gondii, and dissects the 53 effects of individual classes of parasite effectors on host cell biology. 54 55 MAIN TEXT 56 Introduction 57The obligate intracellular parasite Toxoplasma gondii parasitizes a wide range of 58 avian and mammalian organisms, including humans (1). During the acute phase of 59 infection, this unicellular eukaryote rapidly expands within host tissues by penetrating 60 host cells, establishing and replicating within an intracellular parasitophorous vacuole 61 (PV), and simultaneously avoiding clearance by the host immune system (reviewed in 62(2)). To orchestrate these events (Fig. 1A), Toxoplasma employs a vast repertoire of 63 effector proteins housed primarily in two secretory organelles, the rhoptries and dense 64 granules. The rhoptry organelle effectors (ROPs) are secreted by the parasite into the 65 host cytosol during or immediately prior to invasion by an as yet undefined mechanism 66 (reviewed in (3)). The handful of ROPs that have been characterized to date include 67 virulence factors that disrupt immune clearance mechanisms (4-7), remodel the host's 68 cortical actin cytoskeleton at the point of parasite penetration (8, 9), and co-opt the 69 STAT3 and STAT6 pathways (10-12). In contrast, the dense granule effectors (GRAs) 70 are thought to be secr...

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MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to Toxoplasma , Including Counteracting MYR1-Independent Effects

Cited by 57 publications

References 40 publications

Toxoplasmacontrols host cyclin E expression through the use of a novel MYR1-dependent effector protein, HCE1

Toxoplasmacontrols host cyclin E expression through the use of a novel MYR1-dependent effector protein, HCE1

ToxoplasmaGRA15 limits parasite growth in IFNγ-activated fibroblasts through TRAF ubiquitin ligases

Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular ParasiteToxoplasma gondii

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