Corrales, Rosa Milagros, Vincent, Jeremy, Crobu, Lucien et al. (11 more authors) (2025) Tubulin detyrosination shapes Leishmania cytoskeletal architecture and virulence. Proceedings of the National Academy of Sciences of the United States of America. e2415296122. ISSN 1091-6490
Abstract
Tubulin detyrosination has been implicated in various human disorders and is important for regulating microtubule dynamics. While in most organisms this modification is restricted to α-tubulin, in trypanosomatid parasites, it occurs on both α- and β-tubulin. Here, we show that in Leishmania, a single vasohibin (LmVASH) enzyme is responsible for differential kinetics of α- and β-tubulin detyrosination. LmVASH knockout parasites, which are completely devoid of detyrosination, show decreased levels of glutamylation and exhibit a strongly diminished pathogenicity in mice, correlating with decreased proliferation in macrophages. Reduced virulence is associated with altered morphogenesis and flagellum remodeling in detyrosination-deficient amastigotes. Flagellum shortening in the absence of detyrosination is caused by hyperactivity of a microtubule-depolymerizing Kinesin-13 homolog, demonstrating its function as a key reader of the trypanosomatid-tubulin code. Taken together, our work establishes the importance of tubulin detyrosination in remodeling the microtubule-based cytoskeleton required for efficient proliferation in the mammalian host. This highlights tubulin detyrosination as a potential target for therapeutic action against leishmaniasis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 the Author(s). |
Keywords: | Tubulin/metabolism,Animals,Mice,Cytoskeleton/metabolism,Virulence,Protozoan Proteins/metabolism,Microtubules/metabolism,Macrophages/parasitology,Flagella/metabolism,Tyrosine/metabolism,Leishmania/metabolism,Leishmaniasis/parasitology |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 21 Jan 2025 18:18 |
Last Modified: | 13 Mar 2025 05:31 |
Published Version: | https://doi.org/10.1073/pnas.2415296122 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1073/pnas.2415296122 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:222130 |
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Description: Tubulin detyrosination shapes Leishmania cytoskeletalarchitecture and virulence
Licence: CC-BY 2.5