ArticleProceedings of the National Academy of Sciences of the United States of America2010
Expansion of the target of rapamycin (TOR) kinase family and function in Leishmania shows that TOR3 is required for acidocalcisome biogenesis and animal infectivity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 89 citations in OpenAlex.
- Article
- Advances in the cellular biology, biochemistry, and molecular biology of acidocalcisomes.Microbiology and molecular biology reviews : MMBR · 2024Review
- TORC1 is an essential regulator of nutrient-controlled proliferation and differentiation in Leishmania.EMBO reports · 2024Article
- From classical approaches to new developments in genetic engineering of live attenuated vaccine against cutaneous leishmaniasis: potential and immunization.Frontiers in public health · 2024Review
- Live attenuated-nonpathogenicFrontiers in microbiology · 2024Review
- Next-Generation Leishmanization: Revisiting Molecular Targets for Selecting Genetically Engineered Live-AttenuatedMicroorganisms · 2023Review
- Systems biology of autophagy in leishmanial infection and its diverse role in precision medicine.Frontiers in molecular biosciences · 2023Review
- New insights into the role of acidocalcisomes in trypanosomatids.The Journal of eukaryotic microbiology · 2022Review
- Promastigote-to-Amastigote Conversion inPathogens (Basel, Switzerland) · 2022Review
- Characterization of Differentially Abundant Proteins AmongFrontiers in cellular and infection microbiology · 2022Article
- Identification of Potential Kinase Inhibitors within the PI3K/AKT Pathway ofBiomolecules · 2021Article
- Nutrient sensing in Leishmania: Flagellum and cytosol.Molecular microbiology · 2021Review
- The host mTOR pathway and parasitic diseases pathogenesis.Parasitology research · 2021Review
- Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival.Nature communications · 2021Article
- Evidence that a naturally occurring single nucleotide polymorphism in the RagC gene of Leishmania donovani contributes to reduced virulence.PLoS neglected tropical diseases · 2021Article
- In Vitro and in Vivo Activity of mTOR Kinase and PI3K Inhibitors AgainstMolecules (Basel, Switzerland) · 2020Article
- Polyphosphate: A Multifunctional Metabolite in Cyanobacteria and Algae.Frontiers in plant science · 2020Review
- Host-induced gene silencing of BcTOR in Botrytis cinerea enhances plant resistance to grey mould.Molecular plant pathology · 2019Article
- Leishmania tarentolae: Taxonomic classification and its application as a promising biotechnological expression host.PLoS neglected tropical diseases · 2019Review
- TFIIIB Subunit Bdp1 Participates in RNA Polymerase III Transcription in the Protozoan ParasiteBioMed research international · 2019Article
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2 authors at 1 institution in 1 country.
Funding
Abstract
Target of rapamycin (TOR) kinases are key regulators of cell growth, proliferation, and structure in eukaryotes, processes that are highly coordinated during the infectious cycle of eukaryotic pathogens. Database mining revealed three TOR kinases in the trypanosomatid parasite Leishmania major, as defined by homology to the phosphoinositide 3-kinase-related kinase (PIKK) family and a signature conserved FKBP12/rapamycin-binding domain. Consistent with the essential roles of TOR complexes in other organisms, we were unable to generate null TOR1 or TOR2 mutants in cultured L. major promastigotes. In contrast, tor3(-) null mutants were readily obtained; while exhibiting somewhat slower growth, tor3(-) maintained normal morphology, rapamycin sensitivity, and differentiation into the animal-infective metacyclic stage. Significantly, tor3(-) mutants were unable to survive or replicate in macrophages in vitro, or to induce pathology or establish infections in mice in vivo. The loss of virulence was associated with a defect in acidocalcisome formation, as this unique organelle was grossly altered in tor3- mutants and no longer accumulated polyphosphates. Correspondingly, tor3- mutants showed defects in osmoregulation and were sensitive to starvation for glucose but not amino acids, glucose being a limiting nutrient in the parasitophorous vacuole. Thus, in Leishmania, the TOR kinase family has expanded to encompass a unique role in AC function and biology, one that is essential for parasite survival in the mammalian infective stage. Given their important roles in cell survival and virulence, inhibition of TOR kinase function in trypanosomatids offers an attractive target for chemotherapy.
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