The kinesin of the flagellum attachment zone in Leishmania is required for cell morphogenesis, cell division and virulence in the mammalian host

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Abstract
Leishmaniaparasites possess a unique and complex cytoskeletal structure termed flagellum attachment zone (FAZ) connecting the base of the flagellum to one side of the flagellar pocket (FP), an invagination of the cell body membrane and the sole site for endocytosis and exocytosis. This structure is involved in FP architecture and cell morphogenesis, but its precise role and molecular composition remain enigmatic. Here, we characterizedLeishmaniaFAZ7, the only known FAZ protein containing a kinesin motor domain, and part of a clade of trypanosomatid-specific kinesins with unknown functions. The two paralogs of FAZ7, FAZ7A and FAZ7B, display different localizations and functions. FAZ7A localizes at the basal body, while FAZ7B localizes at the distal part of the FP, where the FAZ structure is present inLeishmania. While null mutants of FAZ7A displayed normal growth rates, the deletion of FAZ7B impaired cell growth in both promastigotes and amastigotes ofLeishmania. The kinesin activity is crucial for its function. Deletion of FAZ7B resulted in altered cell division, cell morphogenesis (including flagellum length), and FP structure and function. Furthermore, knocking out FAZ7B induced a mis-localization of two of the FAZ proteins, and disrupted the molecular organization of the FP collar, affecting the localization of its components. Loss of the kinesin FAZ7B has important consequences in the insect vector and mammalian host by reducing proliferation in the sand fly and pathogenicity in mice. Our findings reveal the pivotal role of the only FAZ kinesin as part of the factors important for a successful life cycle ofLeishmania.
Funding Information
  • French LabEx ParaFrap (ANR-11-LABX-0024)
  • French LabEx ParaFrap (ANR-11-LABX-0024)
  • French LabEx ParaFrap (ANR-11-LABX-0024)
  • Centre National de la Recherche Scientifique
  • Centre National de la Recherche Scientifique
  • Centre National de la Recherche Scientifique
  • Horizon 2020 Framework Programme (731060)
  • Horizon 2020 Framework Programme (731060)
  • ERD Funds, project CePaViP (16_019/0000759)
  • ERD Funds, project CePaViP (16_019/0000759)
  • ANR grants LabEx ParaFrap (ANR-11-LABX-0024ANR-20-CE91- 0003, ANR-19-CE17-0014-03)
  • the French National Research Agency (ANR-10-730 INBS-04)

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