A novel hydrolase with a pro-death activity from the protozoan parasite Leishmania major

Apoptosis is a cell death process generally described as involving a cascade of caspase activation, death receptors and/or pro- and antiapoptotic molecules from the BcL-2 family. But about 20 years ago, a caspase-independent apoptotic pathway has been described. Regarding this pathway, we can learn a lot from Leishmania parasites. Indeed, these parasitic protozoa enter, in response to different stimuli, in a form of cell death phenotypically similar to mammalian apoptosis but without involving caspases or death receptors. So far, only two proteins have been clearly identified as being involved in Leishmania-regulated cell death: the metacaspase and the endonuclease G. We report here the identification of a new protein modeled as a potential hydrolase, highly conserved among Leishmania species and absent in the very close parasite Trypanosoma brucei. This protein is involved in L. major-regulated cell death induced by curcumin, miltefosine and pentamidine, after gene overexpression and/or protein translocation to the nucleus. The identification of proteins involved in Leishmania-regulated cell death will provide a better understanding of nonconventional apoptotic pathways in higher eukaryotes. It will also allow the development of new therapeutic tools via the identification of new specific targets.