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Detyrosination of α- and β-tubulin in Leishmania parasites controls the amastigote cytoskeletal architecture and pathogenicity in the mammalian host
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Edité par CCSD -
International audience. Trypanosomatid parasites possess a highly ordered microtubule cytoskeleton that undergoes tubulin post-translational modifications including the removal of a C-terminal tyrosine by a carboxypeptidase vasohibin (VASH) protein. In contrast to mammals, where α-tubulin is the only tyrosinated subunit, Trypanosomatids display a non-canonical C-terminal tyrosine on β-tubulin which is also subjected to detyrosination in Trypanosoma brucei. This peculiarity has the potential to reveal novel and unique regulatory mechanisms important for all Trypanosomatid infections. Here, we explore whether detyrosination is present and functionally relevant in Leishmania parasites. Deletion of VASH abrogates detyrosination of both α- and β-tubulin and correlates with increased levels of tyrosination. Although VASH is dispensable for optimal growth in the (insect) promastigote form, removing its carboxypeptidase activity impairs cell growth in the (mammalian) amastigote form. In the absence of detyrosination, amastigotes display aberrant cell morphology and flagellum remodelling. Moreover, the tip of the short external amastigote flagellum is significantly reduced. This phenotype is restored upon deletion of the microtubule depolymerizing Kinesin-13 enzyme localizing at the flagellum tip. These results provide the first demonstration that readers of the Trypanosomatid-tubulin code exist and are functionally relevant in these parasites. The altered structure of the amastigote flagellum and cell morphology has important consequences in the mammalian host by reducing proliferation in infected macrophages and pathogenicity in mice. These data highlight the importance of detyrosinating both α- and β-tubulin subunits for the virulence of Leishmania parasites in the mammalian host through the remodelling of the amastigote cytoskeletal architecture.
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