Prohibitin and RACK homologues are up-regulated in trypanosomes induced to undergo apoptosis and in naturally occurring terminally differentiated forms

Welburn, Susan C.; Murphy, Noel B.

doi:10.1038/sj.cdd.4400393

Cited by 65 publications

(59 citation statements)

References 25 publications

(43 reference statements)

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“…PCD has been reported for a number of trypanosomatids, with there being evidence for cytoplasmic blebbing, DNA fragmentation, phosphoserine exposure, release of cytochrome C and changes in mitochondrial membrane potential (Ameisen, 1996;Ameisen et al, 1996;Welburn et al, 1996;Das et al, 2001;Zangger et al, 2002;Lee et al, 2002;Holzmuller et al, 2002;Arnoult et al, 2002a;Arnoult et al, 2002b;Sen et al, 2004;Figarella et al, 2005). However, to date there has been only one report of apoptosislike cell death in bloodstream form (BSF) T. brucei (induced by prostaglandin D 2 (Figarella et al, 2005)), whereas PCD apparently resulted from treatment of procyclic form (PCF) T. brucei with the lectin concanavalin A (Welburn et al, 1996;Welburn and Murphy, 1998;Pearson et al, 2000) or reactive oxygen species (Ridgley et al, 1999). Nevertheless, definitive biochemical evidence to support PCD in trypanosomes is lacking and the trypanosome genome appears to lack vital components of two of the central effector pathways of mammalian apoptosis; caspases and their activation, and mitochondrial membrane permeabilization by BCL-2.…”

Section: Introductionmentioning

confidence: 99%

Bloodstream formTrypanosoma bruceidepend upon multiple metacaspases associated with RAB11-positive endosomes

Helms

Ambit

Appleton

et al. 2006

Journal of Cell Science

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Trypanosoma brucei possesses five metacaspase genes. Of these, MCA2 and MCA3 are expressed only in the mammalian bloodstream form of the parasite, whereas MCA5 is expressed also in the insect procyclic form. Triple RNAi analysis showed MCA2, MCA3 and MCA5 to be essential in the bloodstream form, with parasites accumulating pre-cytokinesis. Nevertheless, triple null mutants (Δmca2/3Δmca5) could be isolated after sequential gene deletion. Thereafter, Δmca2/3Δmca5 mutants were found to grow well both in vitro in culture and in vivo in mice. We hypothesise that metacaspases are essential for bloodstream form parasites, but they have overlapping functions and their progressive loss can be compensated for by activation of alternative biochemical pathways. Analysis of Δmca2/3Δmca5 revealed no greater or lesser susceptibility to stresses reported to initiate programmed cell death, such as treatment with prostaglandin D2. The metacaspases were found to colocalise with RAB11, a marker for recycling endosomes. However, variant surface glycoprotein (VSG) recycling processes and the degradation of internalised anti-VSG antibody were found to occur similarly in wild type, Δmca2/3Δmca5 and triple RNAi induced parasites. Thus, the data provide no support for the direct involvement of T. brucei metacaspases in programmed cell death and suggest that the proteins have a function associated with RAB11 vesicles that is independent of known recycling processes of RAB11-positive endosomes.

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Section: Introductionmentioning

confidence: 99%

Bloodstream formTrypanosoma bruceidepend upon multiple metacaspases associated with RAB11-positive endosomes

Helms

Ambit

Appleton

et al. 2006

Journal of Cell Science

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“…In dying Trypanosoma cruzi epimastigotes, elongation factor 1-alpha was shown to relocalise from the cytoplasm into the nucleus 28 whereas in Trypanosoma brucei rhodesiense, prohibitin, an homologue of a mammalian protooncogene and RACK, a receptor for activated protein kinase C, were shown to be up-regulated in procyclic Trypanosoma induced to undergo cell death. 25,29 In Tetrahymena and in Stylonychia, morphological changes and proteins possibly involved in programmed DNA degradation have been described. 8,12,30 However, none of these reports provide answers about the implicated pathways except in the case of death in Trypanosoma brucei, which was shown to be Ca 2+ -dependent when induced by reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis?

2002

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Unicellular organisms, such as the protozoan parasite Leishmania, can be stimulated to show some morphological and biochemical features characteristic of mammalian apoptosis. This study demonstrates that under a variety of stress conditions such as serum deprivation, heat shock and nitric oxide, cell death can be induced leading to genomic DNA fragmentation into oligonucleosomes. DNA fragmentation was observed, without induction, in the infectious stages of the parasite, and correlated with the presence of internucleosomal nuclease activity, visualisation of 45 to 59 kDa nucleases and detection of TUNEL-positive nuclei. DNA fragmentation was not dependent on active effector downstream caspases nor on the lysosomal cathepsin L-like enyzmes CPA and CPB. These data are consistent with the presence of a caspase-independent cell death mechanism in Leishmania, induced by stress and differentiation that differs significantly from metazoa.

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“…Sequences with similarities to RACK1 have recently been identified in Leishmania, Crithidia, and T. brucei (25)(26)(27)(28). In none of these cases is the function known.…”

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confidence: 99%

The RACK1 Homologue from Trypanosoma brucei Is Required for the Onset and Progression of Cytokinesis

Rothberg

Burdette

Pfannstiel

et al. 2006

Journal of Biological Chemistry

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The receptor for activated C kinase 1 (RACK1) is a conserved scaffold protein that helps regulate a range of cell activities including cell growth, shape, and protein translation. We report that a homologue of RACK1 is required for cytokinesis in pathogenic Trypanosoma brucei. The protein, referred to as TRACK, is comprised of WD repeat elements and can complement cpc2 null mutants of Schizosaccharomyces pombe. TRACK is expressed throughout the trypanosome life cycle and is distributed predominantly in a perinuclear region and the cytoplasm but not along the endoplasmic reticulum, mitochondrion, or cleavage furrow of dividing cells. When tetracycline-inducible RNA interference (RNAi) is used to deplete the cellular content of TRACK, the cells remain metabolically active, but growth is inhibited. In bloodstream forms, growth arrest is due to a delay in the onset of cytokinesis. By contrast, procyclic forms are able to initiate cytokinesis in the absence of TRACK but arrest midway through cell cleavage. The RNAi cells undergo multiple rounds of partial cytokinesis and accumulate nuclei and cytoplasmic extensions with attached flagella. The TRACK RNAi construct is also inducible within infected mice. Under these conditions parasites are eliminated from peripheral blood within 3 days post-infection. Taken as a whole, these data indicate that trypanosomes utilize a RACK1 homologue to regulate the final stages of mitosis. Moreover, disrupting the interaction between TRACK and its partners might be targeted in the design of novel therapies.African trypanosomes are protozoan parasites that produce lethal infections in humans and livestock throughout sub-Saharan Africa. Trypanosomes have a complex life cycle that involves changes in morphology, biochemistry, and gene expression as the cells pass through a variety of different environments. Signal cascades are predicted to mediate complex life cycle events and initiate rapid changes in cell behavior. It is hypothesized that ablation of a signal or induction of an inappropriate signal will be lethal to these cells. From past experiments it is clear that trypanosomes have the potential to propagate signals involving Ca 2ϩ , cyclic nucleotides, eicosenoic acid, and phosphoryl transfer (1-4). However, in stark contrast with mammalian cells, where complex interacting signal networks have been described, a simple signal pathway has yet to be identified in Trypanosoma brucei. To remedy this situation we began to study a putative signal anchor protein and the pathways it regulates.In general, anchor proteins help provide spatial organization to the signal process by allowing the formation of multimeric complexes at the appropriate location in the cell (5). Additionally, association with different anchors allows some signal kinases to participate in and distinguish between multiple pathways. The receptor for activated C kinase-1 (RACK1 2 is a WD repeat protein that forms ternary complexes with a range of signal proteins (for review, see Ref. 6). Target proteins interact with RACK1...

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Prohibitin and RACK homologues are up-regulated in trypanosomes induced to undergo apoptosis and in naturally occurring terminally differentiated forms

Cited by 65 publications

References 25 publications

Bloodstream formTrypanosoma bruceidepend upon multiple metacaspases associated with RAB11-positive endosomes

Bloodstream formTrypanosoma bruceidepend upon multiple metacaspases associated with RAB11-positive endosomes

Cell death in Leishmania induced by stress and differentiation: programmed cell death or necrosis?

The RACK1 Homologue from Trypanosoma brucei Is Required for the Onset and Progression of Cytokinesis

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