Tubulin detyrosination shapes <i>Leishmania</i> cytoskeletal architecture and virulence
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Rosa Milagros Corrales
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement
Jeremy Vincent
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement
Lucien Crobu
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement
Rachel Neish
York Biomedical Research Institute, Department of Biology, University of York
Binita Nepal
Department of Pediatrics, University of Texas Southwestern Medical Center
Julien Espeut
Tubulin Code team, Institute of Human Genetics, CNRS, Université Montpellier
Grégoire Pasquier
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement
Ghislain Gillard
Tubulin Code team, Institute of Human Genetics, CNRS, Université Montpellier
Chantal Cazevieille
Université Montpellier, INSERM U1298, Institute for Neurosciences of Montpellier
Jeremy C. Mottram
York Biomedical Research Institute, Department of Biology, University of York
Dawn M. Wetzel
Department of Pediatrics, University of Texas Southwestern Medical Center
Yvon Sterkers
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement
Krzysztof Rogowski
Tubulin Code team, Institute of Human Genetics, CNRS, Université Montpellier
Maude F. Lévêque
Maladies infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle, University of Montpellier, CNRS, Institut de Recherche pour le Développement