El-Fadili, A.K., Zangger, H., Desponds, C., Gonzalez, I.J., Zalila, H., Schaff, C., Ives, A., Masina, S., Mottram, J.C. and Fasel, N. (2010) Cathepsin B-like and cell death in the unicellular human pathogen Leishmania. Cell Death and Disease, 1(e71), pp. 1-9. (doi: 10.1038/cddis.2010.51)
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Publisher's URL: http://dx.doi.org/10.1038/cddis.2010.51
Abstract
In several studies reporting cell death (CD) in lower eukaryotes and in the human protozoan parasite <i>Leishmania</i>, proteolytic activity was revealed using pan-caspase substrates or inhibitors such as carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). However, most of the lower eukaryotes do not encode caspase(s) but MCA, which differs from caspase(s) in its substrate specificity and cannot be accountable for the recognition of Z-VAD-FMK. In the present study, we were interested in identifying which enzyme was capturing the Z-VAD substrate. We show that heat shock (HS) induces <i>Leishmania</i> CD and leads to the intracellular binding of Z-VAD-FMK. We excluded binding and inhibition of Z-VAD-FMK to <i>Leishmania major</i> metacaspase (LmjMCA), and identified cysteine proteinase C (LmjCPC), a cathepsin B-like (CPC) enzyme, as the Z-VAD-FMK binding enzyme. We confirmed the specific interaction of Z-VAD-FMK with CPC by showing that Z-VAD binding is absent in a <i>Leishmania Mexicana</i> strain in which the cpc gene was deleted. We also show that parasites exposed to various stress conditions release CPC into a soluble fraction. Finally, we confirmed the role of CPC in <i>Leishmania</i> CD by showing that, when exposed to the oxidizing agent hydrogen peroxide (H2O2), cpc knockout parasites survived better than wild-type parasites (WT). In conclusion, this study identified CPC as the substrate of Z-VAD-FMK in <i>Leishmania</i> and as a potential additional executioner protease in the CD cascade of <i>Leishmania</i> and possibly in other lower eukaryotes.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Mottram, Professor Jeremy |
| Authors: | El-Fadili, A.K., Zangger, H., Desponds, C., Gonzalez, I.J., Zalila, H., Schaff, C., Ives, A., Masina, S., Mottram, J.C., and Fasel, N. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Cell Death and Disease |
| Publisher: | Nature Publishing Group |
| ISSN: | 2041-4889 |
| Published Online: | 02 September 2010 |
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