Tubulin detyrosination shapes Leishmania cytoskeletal architecture and virulence

• 成果类型: Article
• 署名作者: Corrales, Rosa Milagros; Vincent, Jeremy; Crobu, Lucien; Neish, Rachel; Nepal, Binita; Espeut, Julien; Pasquier, Gregoire; Gillard, Ghislain; Cazevieille, Chantal; Mottram, Jeremy C.; Wetzel, Dawn M.; Sterkers, Yvon; Rogowski, Krzysztof; Leveque, Maude F.
• 署名单位: Institut de Recherche pour le Developpement (IRD); Centre National de la Recherche Scientifique (CNRS); Universite de Montpellier; University of York - UK; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Montpellier
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12498
• DOI: 10.1073/pnas.2415296122
• 发表日期: 2025-01-13
• 关键词: posttranslational modifications; microtubule dynamics; flagellar pocket; tyrosination; mechanisms; aneuploidy; proteins; mexicana; reveals; genes

摘要

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 alpha-tubulin, in trypanosomatid parasites, it occurs on both alpha- and beta-tubulin. Here, we show that in Leishmania, a single vasohibin (LmVASH) enzyme is responsible for differential kinetics of alpha- and beta-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.