An essential role for the Leishmania major metacaspase in cell cycle progression

Ambit, A., Fasel, N., Coombs, G. and Mottram, J. (2008) An essential role for the Leishmania major metacaspase in cell cycle progression. Cell Death and Differentiation, 15(1), pp. 113-122. (doi:10.1038/sj.cdd.4402232)

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Metacaspases (MCAs) are distant orthologues of caspases and have been proposed to play a role in programmed cell death in yeast and plants, but little is known about their function in parasitic protozoa. The MCA gene of Leishmania major (LmjMCA) is expressed in actively replicating amastigotes and procyclic promastigotes, but at a lower level in metacyclic promastigotes. LmjMCA has a punctate distribution throughout the cell in interphase cells, but becomes concentrated in the kinetoplast (mitochondrial DNA) at the time of the organelle's segregation. LmjMCA also translocates to the nucleus during mitosis, where it associates with the mitotic spindle. Overexpression of LmjMCA in promastigotes leads to a severe growth retardation and changes in ploidy, due to defects in kinetoplast segregation and nuclear division and an impairment of cytokinesis. LmjMCA null mutants could not be generated and following genetic manipulation to express LmjMCA from an episome, the only mutants that were viable were those expressing LmjMCA at physiological levels. Together these data suggest that in L. major active LmjMCA is essential for the correct segregation of the nucleus and kinetoplast, functions that could be independent of programmed cell death, and that the amount of LmjMCA is crucial. The absence of MCAs from mammals makes the enzyme a potential drug target against protozoan parasites.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Mottram, Professor Jeremy and Coombs, Professor Graham
Authors: Ambit, A., Fasel, N., Coombs, G., and Mottram, J.
Subjects:Q Science > QR Microbiology
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Death and Differentiation
Publisher:Nature Publishing Group
ISSN (Online):1476-5403
Published Online:28 September 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
297261Post-genomic analysis of cysteine protease function in Leishmania parasitesJeremy MottramMedical Research Council (MRC)G0000508Infection Immunity and Inflammation Life Sciences