Antagonic activities of Trypanosoma cruzi metacaspases affect the balance between cell proliferation, death and differentiation

Abstract

Metacaspases are distant relatives of animal caspases present in plants, fungi and protozoa. At variance with caspases, metacaspases exhibit stringent specificity for basic amino-acid residues and are absolutely dependent on millimolar concentrations of calcium. In the protozoan parasite Trypanosoma cruzi, metacaspases have been suggested to be involved in an apoptosis-like phenomenon upon exposure of the parasite to fresh human serum (FHS). Nuclear relocalization of metacaspases was observed after FHS treatment and overexpression of metacaspase-5 led to enhanced sensitivity to this stimulus. Here we report some biochemical properties of T. cruzi metacaspases. Performing fluorescent-activated cell sorting (FACS) analysis of epimastigotes inducibly overexpressing metacaspase-3, we demonstrate a role for this metacaspase in cell cycle progression, protection of epimastigotes from naturally occurring cell death and differentiation to infective metacyclic trypomastigotes. We also show that regulation of metacaspase-3 activity is important for cell cycle completion inside the mammalian host. On the other hand, inducible overexpression of metacaspase-5 lacking its C-terminal domain caused an apoptotic-like response. These results suggest that the two T. cruzi metacaspases could play an important role in the life cycle and bring to light the close relationship between cell division, death and differentiation in this ancient unicellular eukaryote.

The Arabidopsis METACASPASE9 Degradome

“…Redundant functions in the regulation of senescence-associated death were also shown for two Podospora anserina metacaspases (Hamann et al, 2007) and in the resistance to endoplasmic reticulum stress for two Aspergillus fumigatus metacaspases (Richie et al, 2007). Interestingly, antagonistic functions for homologous metacaspases were found in T. brucei and Arabidopsis in the regulation of cell death events or cell proliferation and differentiation (Coll et al, 2010;Laverrière et al, 2012).…”

The plant metacaspase AtMC1 in pathogen-triggered programmed cell death and aging: functional linkage with autophagy

“…Protozoan metacaspases are involved in cell cycle dynamics 34,[36][37][38] and cell proliferation. 39 The yeast metacaspase Yca1 alters cell cycle dynamics 40 and interestingly, is required for clearance of insoluble protein aggregates, thus contributing to yeast fitness.…”

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

“…Cruzain/cruzipain is a cysteine peptidase required for the survival of T. cruzi. This enzyme, present in all life stages of the trypanosome, has been the focus of several studies and patents and is implicated in parasite cellular entry and digestion of immunoglobulin, immune system evasion, and other cellular mechanisms 19,41 .…”

“…Different classes of peptidases participate in important biological events in the T. cruzi life cycle, including processes of invasion, differentiation, proliferation as well as mechanisms of escape from host immune responses 19 . Thus, peptidase inhibitors are a potential to design trypanocidal drugs.…”