Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for<i>Toxoplasma</i>apical complex biogenesis

Back, Peter; O’Shaughnessy, William; Moon, Andy S; Dewangan, Pravin S; Hu, Xiaoyu; Sha, Jihui; Wohlschlegel, James A.; Bradley, Peter J.; Reese, Michael L.

doi:10.1073/pnas.1921245117

Cited by 46 publications

(80 citation statements)

References 83 publications

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“…The Toxoplasma genome encodes three MAPKs. Two of these kinases have been characterized: TgMAPKL1 (TGME49_312570) prevents centrosome overduplication ( 3 ), and TgERK7 (TGME49_233010) is required for conoid biogenesis ( 22 , 24 ). The gene TGME49_207820 encodes the Toxoplasma ortholog of MAPK2, a MAPK that is specific to and conserved in all alveolates, suggesting a specialized function ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division

O’Shaughnessy

Beraki

et al. 2020

mBio

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Mitogen-activated protein kinases (MAPKs) are a conserved family of protein kinases that regulate signal transduction, proliferation, and development throughout eukaryotes. The apicomplexan parasite Toxoplasma gondii expresses three MAPKs. Two of these, extracellular signal-regulated kinase 7 (ERK7) and MAPKL1, have been implicated in the regulation of conoid biogenesis and centrosome duplication, respectively. The third kinase, MAPK2, is specific to and conserved throughout the Alveolata, although its function is unknown. We used the auxin-inducible degron system to determine phenotypes associated with MAPK2 loss of function in Toxoplasma. We observed that parasites lacking MAPK2 failed to duplicate their centrosomes and therefore did not initiate daughter cell budding, which ultimately led to parasite death. MAPK2-deficient parasites initiated but did not complete DNA replication and arrested prior to mitosis. Surprisingly, the parasites continued to grow and replicate their Golgi apparatus, mitochondria, and apicoplasts. We found that the failure in centrosome duplication is distinct from the phenotype caused by the depletion of MAPKL1. As we did not observe MAPK2 localization at the centrosome at any point in the cell cycle, our data suggest that MAPK2 regulates a process at a distal site that is required for the completion of centrosome duplication and the initiation of parasite mitosis. IMPORTANCE Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that can cause severe and fatal disease in immunocompromised patients and the developing fetus. Rapid parasite replication is critical for establishing a productive infection. Here, we demonstrate that a Toxoplasma protein kinase called MAPK2 is conserved throughout the Alveolata and essential for parasite replication. We found that parasites lacking MAPK2 protein were defective in the initiation of daughter cell budding and were rendered inviable. Specifically, T. gondii MAPK2 (TgMAPK2) appears to be required for centrosome replication at the basal end of the nucleus, and its loss causes arrest early in parasite division. MAPK2 is unique to the Alveolata and not found in metazoa and likely is a critical component of an essential parasite-specific signaling network.

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Section: Resultsmentioning

confidence: 99%

Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division

O’Shaughnessy

Beraki

et al. 2020

mBio

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“…Indeed, even in Toxoplasma the function of the conoid is relatively poorly understood. Most studies of individual protein elements have identified molecules required for its assembly and stability [29,[31][32][33][34][35]. But other studies have implicated roles in control processes, including activating motility and exocytosis, both of which are requirements for invasion as well as host egress events [24,28,30].…”

Section: Discussionmentioning

confidence: 99%

“…The other is that we still know relatively little of the molecular composition of the conoid that would allow the objective testing for the presence of a homologous structure [5]. The conspicuous ultrastructure of conoids such as those of coccidians draw attention to tubulin being a major element, however it is known that there are other conoid proteins responsible for its assembly, stability, and function during invasion [24,[28][29][30][31][32][33][34][35]. To test if a homologous conoid cell feature is present in Aconoidasida, but cryptic by traditional microscopy techniques, fuller knowledge of the molecules that characterise this feature in a 'classic' conoid model is needed.…”

Section: Introductionmentioning

confidence: 99%

Conservation of theToxoplasmaconoid complex proteome reveals a cryptic conoid inPlasmodiumthat differentiates between blood- and vector-stage zoites

Kořený

Zeeshan

Barylyuk

et al. 2020

Preprint

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AbstractThe apical complex is the instrument of invasion used by apicomplexan parasites, and the conoid is a conspicuous feature of this apparatus found throughout this phylum. The conoid, however, is believed to be heavily reduced or missing from Plasmodium species and other members of the Class Aconoidasida. Relatively few conoid proteins have previously been identified, making it difficult to address how conserved this feature is throughout the phylum, and whether it is genuinely missing from some major groups. Moreover, parasites such as Plasmodium species cycle through multiple invasive forms and there is the possibility of differential presence of the conoid between these stages. We have applied spatial proteomics and high-resolution microscopy to develop a more complete molecular inventory and understanding of the organisation of conoid-associated proteins in the model apicomplexan Toxoplasma gondii. These data revealed molecular conservation of all conoid substructures throughout Apicomplexa, including Plasmodium and even in allied Myzozoa, such as Chromera. We reporter-tagged and observed the expression and location of several conoid proteins in the malaria model P. berghei and revealed equivalent structures in all zoite forms, as well as evidence of molecular differentiation between blood-stage merozoites and the ookinetes and sporozoites of the mosquito vector. Collectively we show that the conoid is a conserved apicomplexan element at the heart of the invasion mechanisms of these highly successful and often devastating parasites.

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“…SAS6 is a highly conserved and it is responsible for the cartwheel assembly, crucial for establishing centriole and basal body geometry. One of the homologs is found at the centrosome (TgSAS6) while the other one, named SAS6-Like (TgSAS6L), is located at the conoid, a structure proposed to have emerged from an ancestral MTOC whose original function was to nucleate flagella (Francia et al, 2012;de Leon et al, 2013;Back et al, 2020;O'Shaughnessy et al, 2020). Indeed, de Leon, and col., showed that a SAS6L homolog localizes to the basal body of the flagellated trypanosomatid, Trypanosoma brucei, leading them to propose that SAS6L could exhibit a similar localization in T. gondii (de Leon et al, 2013).…”

Section: Context Of Microgamete Formationmentioning

confidence: 99%

The Structural and Molecular Underpinnings of Gametogenesis in Toxoplasma gondii

Tomasina

Francia

2020

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii is a widely prevalent protozoan parasite member of the phylum Apicomplexa. It causes disease in humans with clinical outcomes ranging from an asymptomatic manifestation to eye disease to reproductive failure and neurological symptoms. In farm animals, and particularly in sheep, toxoplasmosis costs the industry millions by profoundly affecting their reproductive potential. As do all the parasites in the phylum, T. gondii parasites go through sexual and asexual replication in the context of an heteroxenic life cycle involving members of the Felidae family and any warm-blooded vertebrate as definitive and intermediate hosts, respectively. During sexual replication, merozoites differentiate into female and male gametes; their combination gives rise to a zygotes which evolve into sporozoites that encyst and are shed in cat’s feces as environmentally resistant oocysts. During zygote formation T. gondii parasites are diploid providing the parasite with a window of opportunity for genetic admixture making this a key step in the generation of genetic diversity. In addition, oocyst formation and shedding are central to dissemination and environmental contamination with infectious parasite forms. In this minireview we summarize the current state of the art on the process of gametogenesis. We discuss the unique structures of macro and microgametes, an insight acquired through classical techniques, as well as the more recently attained molecular understanding of the routes leading up to these life forms by in vitro and in vivo systems. We pose a number of unanswered questions and discuss these in the context of the latest findings on molecular cues mediating stage switching, and the implication for the field of newly available in vitro tools.

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Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required forToxoplasmaapical complex biogenesis

Cited by 46 publications

References 83 publications

Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division

Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division

Conservation of theToxoplasmaconoid complex proteome reveals a cryptic conoid inPlasmodiumthat differentiates between blood- and vector-stage zoites

The Structural and Molecular Underpinnings of Gametogenesis in Toxoplasma gondii

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