Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages

Wang, Yifan; Sangaré, Lamba Omar; Paredes-Santos, Tatiana C.; Hassan, Musa A.; Krishnamurthy, Shruthi; Furuta, Anna; Markus, Benedikt M.; Lourido, Sebastian

doi:10.1038/s41467-020-18991-8

Cited by 57 publications

(108 citation statements)

References 114 publications

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“…While the specific functions of these proteins are unknown, MYR1–4 all possess predicted transmembrane domains and may form a novel translocon ( Fig 5 ). An additional PV protein known as GRA45 is also required but appears to act broadly as a chaperone supporting dense granule secretion as well as insertion of PVM-resident membrane proteins such as MYR1-4 and thus its contribution to export is likely indirect [ 161 , 163 ]. Finally, ROP17, a kinase injected into the host cell from the rhoptries during invasion, is also necessary for export of dense granule effectors [ 164 ].…”

Section: Perspectives and Future Questionsmentioning

confidence: 99%

Transport mechanisms at the malaria parasite-host cell interface

Beck

2021

PLoS Pathog

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Obligate intracellular malaria parasites reside within a vacuolar compartment generated during invasion which is the principal interface between pathogen and host. To subvert their host cell and support their metabolism, these parasites coordinate a range of transport activities at this membrane interface that are critically important to parasite survival and virulence, including nutrient import, waste efflux, effector protein export, and uptake of host cell cytosol. Here, we review our current understanding of the transport mechanisms acting at the malaria parasite vacuole during the blood and liver-stages of development with a particular focus on recent advances in our understanding of effector protein translocation into the host cell by the Plasmodium Translocon of EXported proteins (PTEX) and small molecule transport by the PTEX membrane-spanning pore EXP2. Comparison to Toxoplasma gondii and other related apicomplexans is provided to highlight how similar and divergent mechanisms are employed to fulfill analogous transport activities.

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Section: Perspectives and Future Questionsmentioning

confidence: 99%

Transport mechanisms at the malaria parasite-host cell interface

Beck

2021

PLoS Pathog

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“…GRA45 was also identified in a CRISPR screen for genes necessary for Toxoplasma tachyzoites to survive in macrophages. This latter work showed that GRA45 has a chaperone‐like domain that is necessary for its role in moving GRAs across the PVM (Wang et al., 2020b). Thus, a total of eight proteins (MYR1‐4, GRA44/45, ROP17, and ASP5) are now known to all be required for this process.…”

Section: Translocation Of Gra Effectors Across the Pvm Is Mediated Bymentioning

confidence: 97%

Seizing control: How dense granule effector proteins enable Toxoplasma to take charge

Panas

Boothroyd

2021

Molecular Microbiology

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Control of the host cell is crucial to the Apicomplexan parasite, Toxoplasma gondii, while it grows intracellularly. To achieve this goal, these single-celled eukaryotes export a series of effector proteins from organelles known as "dense granules" that interfere with normal cellular processes and responses to invasion. While some effectors are found attached to the outer surface of the parasitophorous vacuole (PV) in which Toxoplasma tachyzoites reside, others are found in the host cell's cytoplasm and yet others make their way into the host nucleus, where they alter host transcription. Among the processes that are severely altered are innate immune responses, host cell cycle, and association with host organelles. The ways in which these crucial processes are altered through the coordinated action of a large collection of effectors is as elegant as it is complex, and is the central focus of the following review; we also discuss the recent advances in our understanding of how dense granule effector proteins are trafficked out of the PV. K E Y W O R D Sdense granule, effector protein, innate immunity, toxoplasma | 467 PANAS ANd BOOTHROYd Effector Host cell location Summary of function MYR-dependent GRA16 Nucleus Binds HAUSP, PP2AB55, leads to c-Myc induction, p53 activation, cyclin A degradation, alterations in sterol pathways GRA18 Cytoplasm Binds B-catenin degradation complex preventing B-catenin degradation, upregulates CCL17 and CCL22 GRA24 Nucleus Binds and triggers autophosphorylation of p38 MAPkinase, triggering cytokine production GRA28 Nucleus Upregulates CCL22 HCE1/TEEGR Nucleus Binds to E2F3/4, upregulates cell cycle genes, reduces chromatin access, limits cytokine production TgIST Nucleus Binds STAT1 and Mi2-NuRD complex silencing IGNg responses.

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“…There is a recent systematic review on effector translocation [ 110 ]; therefore, we will focus on updating the information in that review. A recently identified molecular chaperone GRA45, which has structural homology to the α-Crystallin domain of small heat shock protein, is necessary for transporting effector GRAs through the secretory pathway [ 111 ]. When GRA45 is deleted in T. gondii, other dense granule proteins (e.g., GRA5, GRA7, MAF1, GRA23, GRA16, and GRA24) are mislocalized to the vacuolar matrix and fail to be transported to the PVM and beyond [ 111 ].…”

Section: Translocation Of Gra Effectorsmentioning

confidence: 99%

Secreted Effectors Modulating Immune Responses to Toxoplasma gondii

Tomita

Guevara

Shah

et al. 2021

Life

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Toxoplasma gondii is an obligate intracellular parasite that chronically infects a third of humans. It can cause life-threatening encephalitis in immune-compromised individuals. Congenital infection also results in blindness and intellectual disabilities. In the intracellular milieu, parasites encounter various immunological effectors that have been shaped to limit parasite infection. Parasites not only have to suppress these anti-parasitic inflammatory responses but also ensure the host organism’s survival until their subsequent transmission. Recent advancements in T. gondii research have revealed a plethora of parasite-secreted proteins that suppress as well as activate immune responses. This mini-review will comprehensively examine each secreted immunomodulatory effector based on the location of their actions. The first section is focused on secreted effectors that localize to the parasitophorous vacuole membrane, the interface between the parasites and the host cytoplasm. Murine hosts are equipped with potent IFNγ-induced immune-related GTPases, and various parasite effectors subvert these to prevent parasite elimination. The second section examines several cytoplasmic and ER effectors, including a recently described function for matrix antigen 1 (MAG1) as a secreted effector. The third section covers the repertoire of nuclear effectors that hijack transcription factors and epigenetic repressors that alter gene expression. The last section focuses on the translocation of dense-granule effectors and effectors in the setting of T. gondii tissue cysts (the bradyzoite parasitophorous vacuole).

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Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages

Cited by 57 publications

References 114 publications

Transport mechanisms at the malaria parasite-host cell interface

Transport mechanisms at the malaria parasite-host cell interface

Seizing control: How dense granule effector proteins enable Toxoplasma to take charge

Secreted Effectors Modulating Immune Responses to Toxoplasma gondii

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