Characterization and role of protozoan parasite proteasomes

Paugam, A.; Bulteau, Anne Laure; Dupouy‐Camet, Jean; Creuzet, C.; Friguet, Bertrand

doi:10.1016/s1471-4922(02)00064-8

Cited by 59 publications

(42 citation statements)

References 33 publications

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“…Likewise, a proteasome inhibitor, lactacystin, was found to be ineffective in abrogating HePC-induced oligonucleosomal DNA fragmentation. However, lactacystin has been reported to be poorly permeant in Leishmania mexicana promastigotes compared to its ability to permeate amastigotes (40). If the same holds true for L. donovani, the use of an alternative proteasome inhibitor is clearly required before any final conclusion concerning a lack of involvement of this protease complex can be made.…”

Section: Discussionmentioning

confidence: 99%

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Paris¹,

Loiseau²,

Bories³

et al. 2004

Antimicrob Agents Chemother

318

235

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Miltefosine (hexadecylphosphocholine [HePC]) has proved to be a potent oral treatment for human visceral leishmaniasis due to Leishmania donovani. The molecular mechanisms that contribute to the antileishmanial activity of HePC are still unknown. We report that in wild-type promastigotes of Leishmania donovani HePC is able to induce a cell death process with numerous cytoplasmic, nuclear, and membrane features of metazoan apoptosis, including cell shrinkage, DNA fragmentation into oligonucleosome-sized fragments, and phosphatidylserine exposure. None of these changes were detected in an HePC-resistant clone treated with the same drug concentration. Therefore, HePC does not appear to kill L. donovani promastigotes by a direct toxic mechanism but, rather, kills the promastigotes by an indirect one. Pretreatment of wild-type promastigotes with two broad caspase inhibitors, z-Val-Ala-DL-Asp(methoxy)-fluoromethylketone and Boc-Asp(methoxy)-fluoromethylketone, as well as a broad protease inhibitor, calpain inhibitor I, prior to drug exposure interfered with DNA fragmentation but did not prevent cell shrinkage or phosphatidylserine externalization. These data suggest that at least part of the apoptotic machinery operating in wild-type promastigotes involves proteases. Identification of the death-signaling pathways activated in HePC-sensitive parasites appears to be essential for a better understanding of the molecular mechanisms of action and resistance in these parasites.

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Section: Discussionmentioning

confidence: 99%

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Paris¹,

Loiseau²,

Bories³

et al. 2004

Antimicrob Agents Chemother

318

235

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“…1 These values refer to BLASTs carried out with the confidently identified T. cruzi orthologue; BLASTs with the original yeast sequence produced insignificant results for T. brucei and L. mexicana. 2 Partial sequences of the T. cruzi orthologues are available but have not yet been assembled (data not shown). experiments, were calculated using the Jemboss alignment editor.…”

Section: Genomics Of Autophagy In Trypanosomatidsmentioning

confidence: 99%

“…1 This pathway has been studied in many organisms, including trypanosomes and other protozoan parasites (reviewed in ref. 2). The T. brucei proteasome has been analyzed in great detail by Wang and coworkers (e.g., ref.…”

Section: Introductionmentioning

confidence: 99%

Autophagy and Related processes in Trypanosomatids: Insights from Genomic and Bioinformatic Analyses

Herman

Gillies²,

Michels³

et al. 2006

Autophagy

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“…Although Giardia has a proteasome (Paugam et al, 2003), and an active ubiquitin conjugation system (Gallego et al, 2007), Giardia cyclin B is not regulated by ubiquitin-mediated degradation in contrast to all mitotic cyclins characterized to date. Though Sacchoromyces cerevisiae strains have been engineered to complete anaphase and progress to telophase in the absence of an APC (Thornton and Toczyski, 2003) this is the first example of a eukaryotic organism that naturally progresses through the cell cycle without an APC.…”

Section: Introductionmentioning

confidence: 99%

The Giardia cell cycle progresses independently of the Anaphase Promoting Complex

Gourguechon

Holt

Cande

2013

Journal of Cell Science

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SummaryMost cell cycle regulation research has been conducted in model organisms representing a very small part of the eukaryotic domain. The highly divergent human pathogen Giardia intestinalis is ideal for studying the conservation of eukaryotic pathways. Although Giardia has many cell cycle regulatory components, its genome lacks all anaphase-promoting complex (APC) components. In the present study, we show that a single mitotic cyclin in Giardia is essential for progression into mitosis. Strikingly, Giardia cyclin B lacks the conserved N-terminal motif required for timely degradation mediated by the APC and ubiquitin conjugation. Expression of Giardia cyclin B in fission yeast is toxic, leading to a prophase arrest, and this toxicity is suppressed by the addition of a fission yeast degradation motif. Cyclin B is degraded during mitosis in Giardia cells, but this degradation appears to be independent of the ubiquitination pathway. Other putative APC substrates, aurora and polo-like kinases, also show no evidence of ubiquitination. This is the first example of mitosis not regulated by the APC and might reflect an evolutionary ancient form of cell cycle regulation.

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Characterization and role of protozoan parasite proteasomes

Cited by 59 publications

References 33 publications

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Autophagy and Related processes in Trypanosomatids: Insights from Genomic and Bioinformatic Analyses

The Giardia cell cycle progresses independently of the Anaphase Promoting Complex

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