Myburgh, Elmarie orcid.org/0000-0002-2007-5902, Geoghegan, Vincent, Alves-Ferreira, Eliza Vc et al. (5 more authors) (2024) TORC1 is an essential regulator of nutrient-controlled proliferation and differentiation in Leishmania. EMBO Reports. pp. 1075-1105. ISSN 1469-221X
Abstract
Leishmania parasites undergo differentiation between various proliferating and non-dividing forms to adapt to changing host environments. The mechanisms that link environmental cues with the parasite's developmental changes remain elusive. Here, we report that Leishmania TORC1 is a key environmental sensor for parasite proliferation and differentiation in the sand fly-stage promastigotes and for replication of mammalian-stage amastigotes. We show that Leishmania RPTOR1, interacts with TOR1 and LST8, and identify new parasite-specific proteins that interact in this complex. We investigate TORC1 function by conditional deletion of RPTOR1, where under nutrient-rich conditions RPTOR1 depletion results in decreased protein synthesis and growth, G1 cell cycle arrest and premature differentiation from proliferative promastigotes to non-dividing mammalian-infective metacyclic forms. These parasites are unable to respond to nutrients to differentiate into proliferative retroleptomonads, which are required for their blood-meal induced amplification in sand flies and enhanced mammalian infectivity. We additionally show that RPTOR1-/- metacyclic promastigotes develop into amastigotes but do not proliferate in the mammalian host to cause pathology. RPTOR1-dependent TORC1 functionality represents a critical mechanism for driving parasite growth and proliferation.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024. The Author(s). |
Keywords: | Animals,Leishmania,Psychodidae/parasitology,Phlebotomus/parasitology,Nutrients,Cell Proliferation,Mammals |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 20 Dec 2024 15:00 |
Last Modified: | 02 Apr 2025 23:29 |
Published Version: | https://doi.org/10.1038/s44319-024-00084-y |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s44319-024-00084-y |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:221080 |
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Description: TORC1 is an essential regulator of nutrient-controlledproliferation and differentiation in Leishmania
Licence: CC-BY 2.5