title: Cysteine peptidases CPA and CPB are vital for autophagy and differentiation in Leishmania mexicana.
abstract: In the past, ultrastructural investigations of Leishmania mexicana amastigotes revealed structures that were tentatively identified as autophagosomes. This study has now provided definitive data that autophagy occurs in the parasite during differentiation both to metacyclic promastigotes and to amastigotes, autophagosomes being particularly numerous during metacyclic to amastigote form transformation. Moreover, the results demonstrate that inhibiting two major lysosomal cysteine peptidases (CPA and CPB) or removing their genes not only interferes with the autophagy pathway but also prevents metacyclogenesis and transformation to amastigotes, thus adding support to the hypothesis that autophagy is required for cell differentiation. The study suggests that L. mexicana CPA and CPB perform similar roles to the aspartic peptidase PEP4 and the serine peptidase PRB1 in Saccharomyces cerevisiae. The results also provide an explanation for why L. mexicana CPA/CPB-deficient mutants transform to amastigotes very poorly and lack virulence in macrophages and mice.
authors.affiliation: Division of Infection and Immunity, Institute of Biomedical and Life Sciences and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Roderick A
authors.initials: RA
authors.lastname: Williams
authors.forename: Laurence
authors.initials: L
authors.lastname: Tetley
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D007894:Leishmania mexicana / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice; D008815:Mice, Inbred Strains; D008870:Microtubules / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*
chemical_list: D018942:Macrolides; D015800:Protozoan Proteins; C057620:bafilomycin A; C087870:CPa protein, Leishmania mexicana; D003546:Cysteine Endopeptidases