The Role of Metacaspases and Other Proteins Involved in the Apoptosis of Leishmania: Review Article
Abstract
Background: Apoptosis, a determined form of programmed cell death (PCD), occurs in multi-cellular and single-celled organisms. Given that a general understanding of apoptosis in single-cell Leishmania is crucial for designing disease control policies, we reviewed the apoptosis mechanism and the proteins involved.
Methods: The information was obtained from articles published in PubMed, SciELO, Science Direct, Scopus, Google Scholar, and Web of Science databases (1998-2021). Search terms used were” apoptosis” or” Leishmaniasis”.
Results: The 77 subjects were included in the study that revealed the significance of the apoptosis process for Leishmania survival. Although, various stimuli induce Leishmania apoptosis, the proteins involved in apoptosis have been poorly understood. Metacaspases in Leishmania instead of caspase and death receptors in mammals play the same role in the PCD pathways. Also, other apoptotic proteins in Leishmania such as endonuclease G (EndoG), caspases- like cysteine proteases, TSN (Tudor Staphylococcal Nuclease), and Zinnia endonuclease 1 (ZEN1) lead to phenotype similar to mammalian apoptosis. Furthermore, there are differences in these mechanisms between the different species of Leishmania and studies to illustrate downstream events related to the serine phosphatidylcholine exposure, cytochrome C secretion, etc. remain an ongoing challenge.
Conclusion: Determining the essential regulatory proteins in the Leishmania apoptosis and the specific present of metacaspases in parasite, is effective for designing new therapeutic strategies against leishmaniasis and vaccine development.
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4. van Zandbergen G, Lüder CG, Heussler V, et al. Programmed cell death in unicellular parasites: A prerequisite for sustained infection? Trends Parasitol. 2010;26:477-483.
5. Li H, Zhang J, Sun L, et al. Celastrol induces apoptosis and autophagy via the ros/jnk signaling pathway in human osteosarcoma cells: An in vitro and in vivo study. Cell Death Dis. 2015;6:e1604.
6. Arnoult D, Tatischeff I, Estaquier J, et al. On the evolutionary conservation of the cell death pathway: Mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death. Mol Biol Cell. 2001;12:3016-3030.
7. Adams JM, Cory S. The bcl-2 protein family: Arbiters of cell survival. Science. 1998;281:1322-1326.
8. Grassme H, Jendrossek V, Gulbins E. Molecular mechanisms of bacteria induced apoptosis. Apoptosis. 2001;6:441-445.
9. Castanys-Muñoz E, Brown E, Coombs G, et al. Leishmania mexsicana metacaspase is a negative regulator of amastigote proliferation in mammalian cells. Cell Death Dis. 2012;3:e385.
10. Mason EF, Rathmell JC. Cell metabolism: An essential link between cell growth and apoptosis. Biochim Biophys Acta. 2011;1813:645-654.
11. Ambit A, Fasel N, Coombs G, et al. An essential role for the Leishmania major metacaspase in cell cycle progression. Cell Death Differ. 2008;15:113-122.
12. Lee P. Centralization, fragmentation, and replication in the genomic data commons. Governing Medical Knowledge Commons. 2017;100:46-73.
13. Kaczanowski S. Apoptosis: Its origin, history, maintenance and the medical implications for cancer and aging. Phys Biol. 2016;13:031001.
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15. Kaczanowski S, Sajid M, Reece SE. Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites. Parasit Vectors. 2011;4:44.
16. Häcker G. Is there, and should there be, apoptosis in bacteria? Microbes Infect. 2013;15:640-644
17. Sacks D, Kamhawi S. Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu Rev Microbiol. 2001;55:453-483.
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31. Basmaciyan L, Azas N, Casanova M. A potential acetyltransferase involved in Leishmania major metacaspase-dependent cell death. Parasit Vectors. 2019;12:266.
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36. Singh D, Rahi A, Kumari R, et al. Computational and mutational analysis of tatd dnase of bacillus anthracis. J Cell Biochem. 2019;120:11318-11330.
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39. Tuteja R. Emerging functions of helicases in regulation of stress survival in malaria parasite Plasmodium falciparum and their comparison with human host. Parasitol Int. 2016;65:645-664.
40. Klemba M, Goldberg DE. Biological roles of proteases in parasitic protozoa. Annu Rev Biochem. 2002;71:275-305.
41. Arambage SC, Grant KM, Pardo I, et al. Malaria ookinetes exhibit multiple markers for apoptosis-like programmed cell death in vitro. Parasit Vectors. 2009;2:32.
42. Aravind L, Dixit VM, Koonin EV. The domains of death: Evolution of the apoptosis machinery. Trends Biochem Sci. 1999;24:47-53.
43. Carmona-Gutierrez D, Fröhlich K, Kroemer G, et al. Metacaspases are caspases. Doubt no more. Cell Death Differ. 2010;17:377-378.
44. Uren AG, O'Rourke K, Aravind LA, et al. Identification of paracaspases and metacaspases: Two ancient families of caspase-like proteins, one of which plays a key role in malt lymphoma. Mol Cell. 2000;6:961-967.
45. Meslin B, Zalila H, Fasel N, et al. Are protozoan metacaspases potential parasite killers? Parasit Vectors. 2011;4:26.
46. Minina EA, Coll NS, Tuominen H, et al. Metacaspases versus caspases in development and cell fate regulation. Cell Death Differ. 2017;24:1314-1325.
47. González IJ, Desponds C, Schaff C, et al. Leishmania major metacaspase can replace yeast metacaspase in programmed cell death and has arginine-specific cysteine peptidase activity. Int J Parasitol. 2007;37:161-172.
48. Vercammen D, Belenghi B, Van De Cotte B, et al. Serpin1 of Arabidopsis thaliana is a suicide inhibitor for metacaspase 9. J Mol Biol. 2006;364:625-636.
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50. Singh AP, Singh J, Sharma R, et al. Biochemical characterization of unusual cysteine protease of P. falciparum, metacaspase-2 (mca-2). Mol Biochem Parasitol. 2018;220:28-41.
51. Jimenez F, Aiba‐Masago S, Al Hashimi I, et al. Activated caspase 3 and cleaved poly (adp‐ribose) polymerase in salivary epithelium suggest a pathogenetic mechanism for sjögren's syndrome. Rheumatology (Oxford). 2002;41:338-342.
52. Das M, Mukherjee SB, Shaha C. Hydrogen peroxide induces apoptosis-like death in Leishmania donovani promastigotes. J Cell Sci. 2001;114:2461-2469.
53. Ojha M, Cattaneo A, Hugh S, et al. Structure, expression and function of Allomyces arbuscula cdp ii (metacaspase) gene. Gene. 2010;457:25-34.
54. He R, Drury GE, Rotari VI, Gordon A, et al. Metacaspase-8 modulates programmed cell death induced by ultraviolet light and h2o2 in arabidopsis. J Biol Chem. 2008;283:774-783.
55. Tsiatsiani L, Van Breusegem F, Gallois P, et al. Metacaspases. Cell Death Differ. 2011;18:1279-1288.
56. Zalila H, González IJ, El‐Fadili AK, et al. Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major. Mol Microbiol. 2011;79:222-239.
57. Zangger H, Mottram J, Fasel N. Cell death in Leishmania induced by stress and differentiation: Programmed cell death or necrosis? Cell Death Differ. 2002;9:1126-1139.
58. Kumar B, Verma S, Kashif M, et al. Metacaspase-3 of Plasmodium falciparum: An atypical trypsin-like serine protease. Int J Biol Macromol. 2019;138:309-320.
59. Jiménez IG. " Leishmania Major" Metacaspase in Programmed Cell Death (Doctoral dissertation, éditeur non identifié), 2007.
60. Raina P, Kaur S. Knockdown of ldmc1 and hsp70 by antisense oligonucleotides causes cell-cycle defects and programmed cell death in Leishmania donovani. Mol Cell Biochem. 2012;359:135-149.
61. Kosec G, Alvarez VE, Agüero F, et al. Metacaspases of Trypanosoma cruzi: Possible candidates for programmed cell death mediators. Mol Biochem Parasitol. 2006;145:18-28.
62. McLuskey K, Rudolf J, Proto WR, et al. Crystal structure of a Trypanosoma brucei metacaspase. Proc Natl Acad Sci U S A. 2012;109:7469-7474.
63. Madeo F, Herker E, Maldener C, et al. A caspase-related protease regulates apoptosis in yeast. Mol Cell. 2002;9:911-917.
64. Reape TJ, McCabe PF. Apoptotic-like regulation of programmed cell death in plants. Apoptosis. 2010;15:249-256.
65. Helms MJ, Ambit A, Appleton P, et al. Bloodstream form Trypanosoma brucei depend upon multiple metacaspases associated with rab11-positive endosomes. J Cell Sci. 2006;119:1105-1117.
66. Figarella K, Rawer M, Uzcategui N, et al. Prostaglandin d2 induces programmed cell death in Trypanosoma brucei bloodstream form. Cell Death Differ. 2005;12:335-346.
67. Coll NS, Vercammen D, Smidler A, et al. Arabidopsis type i metacaspases control cell death. Science. 2010;330:1393-1397.
68. Atkinson HJ, Babbitt PC, Sajid M. The global cysteine peptidase landscape in parasites. Trends Parasitol. 2009;25:573-581.
69. Watanabe N, Lam E. Two arabidopsis metacaspases atmcp1b and atmcp2b are arginine/lysine-specific cysteine proteases and activate apoptosis-like cell death in yeast. J Biol Chem. 2005;280:14691-14699.
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2. Meier P, Finch A, Evan G. Apoptosis in development. Nature. 2000;407:796-801.
3. Lee N, Bertholet S, Debrabant A, et al. Programmed cell death in the unicellular protozoan parasite Leishmania. Cell Death Differ. 2002;9:53-64.
4. van Zandbergen G, Lüder CG, Heussler V, et al. Programmed cell death in unicellular parasites: A prerequisite for sustained infection? Trends Parasitol. 2010;26:477-483.
5. Li H, Zhang J, Sun L, et al. Celastrol induces apoptosis and autophagy via the ros/jnk signaling pathway in human osteosarcoma cells: An in vitro and in vivo study. Cell Death Dis. 2015;6:e1604.
6. Arnoult D, Tatischeff I, Estaquier J, et al. On the evolutionary conservation of the cell death pathway: Mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death. Mol Biol Cell. 2001;12:3016-3030.
7. Adams JM, Cory S. The bcl-2 protein family: Arbiters of cell survival. Science. 1998;281:1322-1326.
8. Grassme H, Jendrossek V, Gulbins E. Molecular mechanisms of bacteria induced apoptosis. Apoptosis. 2001;6:441-445.
9. Castanys-Muñoz E, Brown E, Coombs G, et al. Leishmania mexsicana metacaspase is a negative regulator of amastigote proliferation in mammalian cells. Cell Death Dis. 2012;3:e385.
10. Mason EF, Rathmell JC. Cell metabolism: An essential link between cell growth and apoptosis. Biochim Biophys Acta. 2011;1813:645-654.
11. Ambit A, Fasel N, Coombs G, et al. An essential role for the Leishmania major metacaspase in cell cycle progression. Cell Death Differ. 2008;15:113-122.
12. Lee P. Centralization, fragmentation, and replication in the genomic data commons. Governing Medical Knowledge Commons. 2017;100:46-73.
13. Kaczanowski S. Apoptosis: Its origin, history, maintenance and the medical implications for cancer and aging. Phys Biol. 2016;13:031001.
14. Debrabant A, Lee N, Bertholet S, et al. Programmed cell death in trypanosomatids and other unicellular organisms. Int J Parasitol. 2003;33:257-267.
15. Kaczanowski S, Sajid M, Reece SE. Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites. Parasit Vectors. 2011;4:44.
16. Häcker G. Is there, and should there be, apoptosis in bacteria? Microbes Infect. 2013;15:640-644
17. Sacks D, Kamhawi S. Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu Rev Microbiol. 2001;55:453-483.
18. Das P, Alam MN, Paik D, et al. Protease inhibitors in potential drug development for leishmaniasis. Indian J Biochem Biophys. 2013 Oct;50(5):363-76.
19. Chandra S, Ruhela D, Deb A, Vishwakarma RA. Glycobiology of the Leishmania parasite and emerging targets for antileishmanial drug discovery. Expert Opin Ther Targets. 2010;14:739-757.
20. Solano-Gálvez S-G, Álvarez-Hernández D-A, Gutiérrez-Kobeh L, et al. Leishmania: Manipulation of signaling pathways to inhibit host cell apoptosis. Ther Adv Infect Dis. 2021;8:20499361211014977.
21. Gannavaram S, Debrabant A. Programmed cell death in Leishmania: Biochemical evidence and role in parasite infectivity. Front Cell Infect Microbiol. 2012;2:95.
22. Duncan R, Gannavaram S, Dey R, et al. Identification and characterization of genes involved in Leishmania pathogenesis: The potential for drug target selection. Mol Biol Int. 2011;2011:428486.
23. Michalkova V, Benoit JB, Weiss BL, et al. Vitamin b6 generated by obligate symbionts is critical for maintaining proline homeostasis and fecundity in tsetse flies. Appl Environ Microbiol. 2014;80:5844-5853.
24. Van Zandbergen G, Bollinger A, Wenzel A, et al. Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum. Proc Natl Acad Sci U S A. 2006;103:13837-13842.
25. Basmaciyan L, Casanova M. Cell death in Leishmania. Parasite. 2019; 26:71.
26. Das P, Saha S, BoseDasgupta S. The ultimate fate determinants of drug induced cell-death mechanisms in trypanosomatids. Int J Parasitol Drugs Drug Resist. 2021;15:81-91.
27. Basmaciyan L, Azas N, Casanova M. Different apoptosis pathways in Leishmania parasites. Cell Death Discov. 2018; 4:27.
28. Li LY, Luo X, Wang X. Endonuclease g is an apoptotic dnase when released from mitochondria. Nature. 2001;412:95-99.
29. Lee N, Gannavaram S, Selvapandiyan A, et al. Characterization of metacaspases with trypsin-like activity and their putative role in programmed cell death in the protozoan parasite Leishmania. Eukaryot Cell. 2007;6:1745-1757.
30. Proto WR, Coombs GH, Mottram JC. Cell death in parasitic protozoa: Regulated or incidental? Nat Rev Microbiol. 2013;11:58-66.
31. Basmaciyan L, Azas N, Casanova M. A potential acetyltransferase involved in Leishmania major metacaspase-dependent cell death. Parasit Vectors. 2019;12:266.
32. Laverriere M, Cazzulo JJ, Alvarez VE. Antagonic activities of Trypanosoma cruzi metacaspases affect the balance between cell proliferation, death and differentiation. Cell Death Differ. 2012;19:1358-1369.
33. Gannavaram S, Vedvyas C, Debrabant A. Conservation of the pro-apoptotic nuclease activity of endonuclease g in unicellular trypanosomatid parasites. J Cell Sci. 2008;121:99-109.
34. BoseDasgupta S, Das B, Sengupta S, et al. The caspase-independent algorithm of programmed cell death in Leishmania induced by baicalein: The role of ldendog, ldfen-1 and ldtatd as a DNA ‘degradesome’. Cell Death Differ. 2008;15:1629-1640.
35. Gannavaram S, Debrabant A. Involvement of tatd nuclease during programmed cell death in the protozoan parasite trypanosoma brucei. Mol Microbiol. 2012;83:926-935.
36. Singh D, Rahi A, Kumari R, et al. Computational and mutational analysis of tatd dnase of bacillus anthracis. J Cell Biochem. 2019;120:11318-11330.
37. Sundström JF, Vaculova A, Smertenko AP, et al. Tudor staphylococcal nuclease is an evolutionarily conserved component of the programmed cell death degradome. Nat Cell Biol. 2009;11:1347-1354.
38. Broadhurst M, Wheeler T. The p100 coactivator is present in the nuclei of mammary epithelial cells and its abundance is increased in response to prolactin in culture and in mammary tissue during lactation. J Endocrinol. 2001;171:329-337.
39. Tuteja R. Emerging functions of helicases in regulation of stress survival in malaria parasite Plasmodium falciparum and their comparison with human host. Parasitol Int. 2016;65:645-664.
40. Klemba M, Goldberg DE. Biological roles of proteases in parasitic protozoa. Annu Rev Biochem. 2002;71:275-305.
41. Arambage SC, Grant KM, Pardo I, et al. Malaria ookinetes exhibit multiple markers for apoptosis-like programmed cell death in vitro. Parasit Vectors. 2009;2:32.
42. Aravind L, Dixit VM, Koonin EV. The domains of death: Evolution of the apoptosis machinery. Trends Biochem Sci. 1999;24:47-53.
43. Carmona-Gutierrez D, Fröhlich K, Kroemer G, et al. Metacaspases are caspases. Doubt no more. Cell Death Differ. 2010;17:377-378.
44. Uren AG, O'Rourke K, Aravind LA, et al. Identification of paracaspases and metacaspases: Two ancient families of caspase-like proteins, one of which plays a key role in malt lymphoma. Mol Cell. 2000;6:961-967.
45. Meslin B, Zalila H, Fasel N, et al. Are protozoan metacaspases potential parasite killers? Parasit Vectors. 2011;4:26.
46. Minina EA, Coll NS, Tuominen H, et al. Metacaspases versus caspases in development and cell fate regulation. Cell Death Differ. 2017;24:1314-1325.
47. González IJ, Desponds C, Schaff C, et al. Leishmania major metacaspase can replace yeast metacaspase in programmed cell death and has arginine-specific cysteine peptidase activity. Int J Parasitol. 2007;37:161-172.
48. Vercammen D, Belenghi B, Van De Cotte B, et al. Serpin1 of Arabidopsis thaliana is a suicide inhibitor for metacaspase 9. J Mol Biol. 2006;364:625-636.
49. Aravind L, Koonin EV. Classification of the caspase–hemoglobinase fold: Detection of new families and implications for the origin of the eukaryotic separins. Proteins. 2002;46:355-367.
50. Singh AP, Singh J, Sharma R, et al. Biochemical characterization of unusual cysteine protease of P. falciparum, metacaspase-2 (mca-2). Mol Biochem Parasitol. 2018;220:28-41.
51. Jimenez F, Aiba‐Masago S, Al Hashimi I, et al. Activated caspase 3 and cleaved poly (adp‐ribose) polymerase in salivary epithelium suggest a pathogenetic mechanism for sjögren's syndrome. Rheumatology (Oxford). 2002;41:338-342.
52. Das M, Mukherjee SB, Shaha C. Hydrogen peroxide induces apoptosis-like death in Leishmania donovani promastigotes. J Cell Sci. 2001;114:2461-2469.
53. Ojha M, Cattaneo A, Hugh S, et al. Structure, expression and function of Allomyces arbuscula cdp ii (metacaspase) gene. Gene. 2010;457:25-34.
54. He R, Drury GE, Rotari VI, Gordon A, et al. Metacaspase-8 modulates programmed cell death induced by ultraviolet light and h2o2 in arabidopsis. J Biol Chem. 2008;283:774-783.
55. Tsiatsiani L, Van Breusegem F, Gallois P, et al. Metacaspases. Cell Death Differ. 2011;18:1279-1288.
56. Zalila H, González IJ, El‐Fadili AK, et al. Processing of metacaspase into a cytoplasmic catalytic domain mediating cell death in Leishmania major. Mol Microbiol. 2011;79:222-239.
57. Zangger H, Mottram J, Fasel N. Cell death in Leishmania induced by stress and differentiation: Programmed cell death or necrosis? Cell Death Differ. 2002;9:1126-1139.
58. Kumar B, Verma S, Kashif M, et al. Metacaspase-3 of Plasmodium falciparum: An atypical trypsin-like serine protease. Int J Biol Macromol. 2019;138:309-320.
59. Jiménez IG. " Leishmania Major" Metacaspase in Programmed Cell Death (Doctoral dissertation, éditeur non identifié), 2007.
60. Raina P, Kaur S. Knockdown of ldmc1 and hsp70 by antisense oligonucleotides causes cell-cycle defects and programmed cell death in Leishmania donovani. Mol Cell Biochem. 2012;359:135-149.
61. Kosec G, Alvarez VE, Agüero F, et al. Metacaspases of Trypanosoma cruzi: Possible candidates for programmed cell death mediators. Mol Biochem Parasitol. 2006;145:18-28.
62. McLuskey K, Rudolf J, Proto WR, et al. Crystal structure of a Trypanosoma brucei metacaspase. Proc Natl Acad Sci U S A. 2012;109:7469-7474.
63. Madeo F, Herker E, Maldener C, et al. A caspase-related protease regulates apoptosis in yeast. Mol Cell. 2002;9:911-917.
64. Reape TJ, McCabe PF. Apoptotic-like regulation of programmed cell death in plants. Apoptosis. 2010;15:249-256.
65. Helms MJ, Ambit A, Appleton P, et al. Bloodstream form Trypanosoma brucei depend upon multiple metacaspases associated with rab11-positive endosomes. J Cell Sci. 2006;119:1105-1117.
66. Figarella K, Rawer M, Uzcategui N, et al. Prostaglandin d2 induces programmed cell death in Trypanosoma brucei bloodstream form. Cell Death Differ. 2005;12:335-346.
67. Coll NS, Vercammen D, Smidler A, et al. Arabidopsis type i metacaspases control cell death. Science. 2010;330:1393-1397.
68. Atkinson HJ, Babbitt PC, Sajid M. The global cysteine peptidase landscape in parasites. Trends Parasitol. 2009;25:573-581.
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| Files | ||
| Issue | Vol 20 No 1 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| Leishmania Apoptosis Metacaspases | ||
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How to Cite
1.
Aghaei M, Aghaei S, Shahmoradi Z, Hejazi SH. The Role of Metacaspases and Other Proteins Involved in the Apoptosis of Leishmania: Review Article. Iran J Parasitol. 2025;20(1):1-12.
