Tubulin detyrosination shapes Leishmania cytoskeletal architecture and virulence

TY - JOUR

T1 - Tubulin detyrosination shapes Leishmania cytoskeletal architecture and virulence

AU - Corrales, Rosa Milagros

AU - Vincent, Jeremy

AU - Crobu, Lucien

AU - Neish, Rachel

AU - Nepal, Binita

AU - Espeut, Julien

AU - Pasquier, Grégoire

AU - Gillard, Ghislain

AU - Cazevieille, Chantal

AU - Mottram, Jeremy C

AU - Wetzel, Dawn M

AU - Sterkers, Yvon

AU - Rogowski, Krzysztof

AU - Lévêque, Maude F

N1 - © 2025 the Author(s).

PY - 2025/1/14

Y1 - 2025/1/14

N2 - 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.

AB - 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.

KW - Tubulin/metabolism

KW - Animals

KW - Mice

KW - Cytoskeleton/metabolism

KW - Virulence

KW - Protozoan Proteins/metabolism

KW - Microtubules/metabolism

KW - Macrophages/parasitology

KW - Flagella/metabolism

KW - Tyrosine/metabolism

KW - Leishmania/metabolism

KW - Leishmaniasis/parasitology

U2 - 10.1073/pnas.2415296122

DO - 10.1073/pnas.2415296122

M3 - Article

C2 - 39808657

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 3

M1 - e2415296122

ER -