Abstract
We investigate the role of methionine aminopeptidase 2 (MAP2) in miltefosine induced programmed cell death (PCD) in promastigote form of L. donovani. We report that TNP-470, an inhibitor of MAP2, inhibits programmed cell death in miltefosine treated promastigotes. It inhibits the biochemical features of metazoan apoptosis, including caspase3/7 protease like activity, oligonucleosomal DNA fragmentation, collapse of mitochondrial transmembrane potential, and increase in cytosolic pool of calcium ions but did not prevent the cell death and phosphatidyl serine externalization. The data suggests that the MAP2 is involved in the regulation of PCD in parasite. Moreover, TNP-470 shows the leishmanicidal activity (IC50 = 15 µM) and in vitro inhibition of LdMAP2 activity (Ki = 13.5 nM). Further studies on MAP2 and identification of death signaling pathways provide valuable information that could be exploited to understand the role of non caspase proteases in PCD of L. donovani.
Highlights
Apoptotic like cell death in Leishmania and other unicellular organisms after drug treatment or under stress conditions is well characterized[1,2,3,4,5]
The treatment of L. donovani promastigote cells with miltefosine induced the over-expression of methionine aminopeptidase 2 (MAP2) by 3.5 times compared to control cells[20]
This finding suggests the involvement of MAP2 in apoptosis like cell death of the parasite and prompted us to study the role of MAP2 in the apoptotic processes of Leishmania parasite
Summary
Apoptotic like cell death in Leishmania and other unicellular organisms after drug treatment or under stress conditions is well characterized[1,2,3,4,5]. Role of other proteases in apoptotic like cell death in Leishmania is not yet extensively studied. The treatment of L. donovani promastigote cells with miltefosine induced the over-expression of methionine aminopeptidase 2 (MAP2) by 3.5 times compared to control cells[20]. This finding suggests the involvement of MAP2 in apoptosis like cell death of the parasite and prompted us to study the role of MAP2 in the apoptotic processes of Leishmania parasite. We have successfully demonstrated that a specific MAP2 inhibitor prevents miltefosine induced apoptotic features like increased caspase3/7 protease like activity, DNA degradation, disruption in transmembrane potential of mitochondria, and increase in cytosolic calcium
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