An Easily Dissociated 26 S Proteasome Catalyzes an Essential Ubiquitin-mediated Protein Degradation Pathway in Trypanosoma brucei

Li, Ziyin; Zou, Chun Bin; Yao, Yi; Hoyt, M. Andrew; McDonough, Stephen; Mackey, Zachary B.; Coffino, Philip; Wang, Ching C.

doi:10.1074/jbc.m109029200

Cited by 62 publications

(72 citation statements)

References 54 publications

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“…4). Surprisingly, down-regulated expression of PA26 does not affect the in vitro growth of the procyclic form of T. brucei (29), suggesting that other forms of the proteasome may exist that can compensate for the lack of 11 S regulator complexes.…”

Section: Discussionmentioning

confidence: 99%

“…First, mouse ornithine decarboxylase expressed in T. brucei together with a rat antizyme was found to be highly stable (27), whereas this same protein complex is rapidly degraded by the 26 S proteasome in mammalian cells (28). Second, down-regulation of expression of each of the 7 ␣-subunits, 7 ␤-subunits, the 6 ATPase subunits, and the 11 non-ATPase subunits of the 26 S proteasome by RNA interference in T. brucei leads to intracellular accumulation of ubiquitinated proteins and blocked cell growth (29,30). Third, the 11 S regulator PA26 -20 S proteasome complex constitutes the predominant complex in T. brucei (31), yet a down-regulation of PA26 expression by RNA interference results in no detectable phenotype in the insect form of T. brucei (29).…”

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confidence: 99%

“…Second, down-regulation of expression of each of the 7 ␣-subunits, 7 ␤-subunits, the 6 ATPase subunits, and the 11 non-ATPase subunits of the 26 S proteasome by RNA interference in T. brucei leads to intracellular accumulation of ubiquitinated proteins and blocked cell growth (29,30). Third, the 11 S regulator PA26 -20 S proteasome complex constitutes the predominant complex in T. brucei (31), yet a down-regulation of PA26 expression by RNA interference results in no detectable phenotype in the insect form of T. brucei (29). Thus, it is not clear how the various forms of proteasome in T. brucei are regulated for coordinated protein degradation, cell cycle progression, and development of T. brucei.…”

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Biochemical Analysis of the 20 S Proteasome of Trypanosoma brucei

Wang

Bozdech

Liu

et al. 2003

Journal of Biological Chemistry

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We describe here biochemical characterization of the 20 S proteasome from the parasitic protozoan Trypanosoma brucei. Similar to the mammalian proteasome, the T. brucei proteasome is made up of seven ␣-and seven ␤-subunits. Of the seven ␤-type subunits, five contain pro-sequences that are proteolytically removed during assembly, and three of them are predicted to be catalytic based on primary sequence. Affinity labeling studies revealed that, unlike the mammalian proteasome where three ␤-subunits were labeled by the affinity reagents, only two ␤-subunits of the T. brucei proteasome were labeled in the complex. These two subunits corresponded to ␤2 and ␤5 subunits responsible for the trypsin-like and chymotrypsin-like proteolytic activities, respectively. Screening of a library of 137,180 tetrapeptide fluorogenic substrates against the T. brucei 20 S proteasome confirmed the nominal ␤1-subunit (caspase-like or PGPH) activity and identified an overall substrate preference for hydrophobic residues at the P1 to P4 positions in a substrate. This overall stringency is relaxed in the 11 S regulator (PA26)-20 S proteasome complex, which shows both appreciable activities for cleavage after acidic amino acids and a broadened activity for cleavage after basic amino acids. The 20 S proteasome from T. brucei also shows appreciable activity for cleavage after P1-Gln that is minimally observed in the human counterpart. These results demonstrate the importance of substrate sequence specificity of the T. brucei proteasome and highlight its biochemical divergence from the human enzyme.

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Section: Discussionmentioning

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Biochemical Analysis of the 20 S Proteasome of Trypanosoma brucei

Wang

Bozdech

Liu

et al. 2003

Journal of Biological Chemistry

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“…The T. brucei proteasome has been analyzed in great detail by Wang and coworkers (e.g., ref. 3). Although autophagy too has been the subject of intense research during recent years, this work remained essentially limited to different yeasts, with their great possibilities for application of genetic approaches, and to a lesser extent to mammalian cells.…”

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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“…Proteasomes are large, non-lysosomal, multi-subunit protease complexes. They are characterised by evolutionarily conserved proteins and are present in Trypanosoma brucei [8], Trypanosoma cruzi [9], Toxoplasma gondii [10], Plasmodium spp. [11], Entamoeba histolytica and Entamoeba invadens [12], as well as in Leishmania mexicana [13].…”

Section: Introductionmentioning

confidence: 99%

Antileishmanial activity of HIV protease inhibitors

Savoia

Allice

Tovo

2005

International Journal of Antimicrobial Agents

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The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD 50 ) values of, respectively, 8.3 M and 7 M on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.

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An Easily Dissociated 26 S Proteasome Catalyzes an Essential Ubiquitin-mediated Protein Degradation Pathway in Trypanosoma brucei

Cited by 62 publications

References 54 publications

Biochemical Analysis of the 20 S Proteasome of Trypanosoma brucei

Biochemical Analysis of the 20 S Proteasome of Trypanosoma brucei

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

Antileishmanial activity of HIV protease inhibitors

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