Tubulin detyrosination shapes Leishmania cytoskeletal architecture and virulence

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Milagros Corrales, Rosa | Vincent, Jeremy | Crobu, Lucien | Neish, Rachel | Nepal, Binita | Espeut, Julien | Pasquier, Grégoire | Gillard, Ghislain | Cazevieille, Chantal | Mottram, Jeremy | Wetzel, Dawn | Sterkers, Yvon | Rogowski, Krzysztof | Lévêque, Maude

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International audience. 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 detyrosination. LmVASH knockout parasites are completely devoid of detyrosination and show decreased levels of tubulin glutamylation. Loss of detyrosination alters microtubule dynamics resulting in impaired developmental morphogenesis. Detyrosination-deficient amastigotes display altered cell division, morphology and flagellum remodeling that was associated with diminished proliferation in macrophages and pathogenicity in mice. We show that the microtubule depolymerizing Kinesin-13.2 is a functionally relevant reader of the “tubulin code” required for flagellum shortening. Taken together, our work establishes the importance of tubulin detyrosination in remodeling the microtubule-based cytoskeleton that is required for efficient infection and proliferation in the mammalian host.

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