title: Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major.
abstract: Metacaspases are cysteine peptidases that could play a role similar to caspases in the cell death programme of plants, fungi and protozoa. The human protozoan parasite Leishmania major expresses a single metacaspase (LmjMCA) harbouring a central domain with the catalytic dyad histidine and cysteine as found in caspases. In this study, we investigated the processing sites important for the maturation of LmjMCA catalytic domain, the cellular localization of LmjMCA polypeptides, and the functional role of the catalytic domain in the cell death pathway of Leishmania parasites. Although LmjMCA polypeptide precursor form harbours a functional mitochondrial localization signal (MLS), we determined that LmjMCA polypeptides are mainly localized in the cytoplasm. In stress conditions, LmjMCA precursor forms were extensively processed into soluble forms containing the catalytic domain. This domain was sufficient to enhance sensitivity of parasites to hydrogen peroxide by impairing the mitochondrion. These data provide experimental evidences of the importance of LmjMCA processing into an active catalytic domain and of its role in disrupting mitochondria, which could be relevant in the design of new drugs to fight leishmaniasis and likely other protozoan parasitic diseases.
authors.affiliation: Department of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, 1066 Epalinges, Switzerland.
authors.forename: Habib
authors.initials: H
authors.lastname: Zalila
authors.forename: Iveth J
authors.initials: IJ
authors.lastname: González
authors.forename: Amal Kuendig
authors.initials: AK
authors.lastname: El-Fadili
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Delgado
authors.forename: Chantal
authors.initials: C
authors.lastname: Desponds
authors.forename: Cédric
authors.initials: C
authors.lastname: Schaff
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fasel
mesh_terms: D000595:Amino Acid Sequence; D020169:Caspases / Q000378:metabolism*; D020134:Catalytic Domain; D016923:Cell Death; D003593:Cytoplasm / Q000201:enzymology; D018320:Leishmania major / Q000201:enzymology* / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D020169:Caspases