Potential role of autophagy in proteolysis in Trichomonas vaginalis

Huang, Kuo‐Yang; Chen, Ruei-Min; Lin, Hsin‐Chung; Cheng, Wei-Hung; Lin, Hsin‐An; Lin, Wei‐Ning; Huang, Po-Jung; Chiu, Cheng-Hsun; Tang, Petrus

doi:10.1016/j.jmii.2018.11.002

Cited by 13 publications

(22 citation statements)

References 30 publications

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“…As for P. falciparum, treatment of T. vaginalis for only 1 h with proteasome inhibitors resulted in a significant accumulation of ubiquitinated proteins, suggesting that cell death in this parasite may occur by a mechanism similar to that in P. falciparum. Furthermore, depending on growth conditions, inhibition of the proteasome may also induce autophagy in T. vaginalis, which, if excessive, could induce cell death (28).…”

Section: Discussionmentioning

confidence: 99%

“…The parasite, like all eukaryotic cells, also produces proteasome subunits, but their importance for parasite growth and survival is poorly defined. Short-term incubation with a proteasome inhibitor leads to autophagy in T. vaginalis under glucose-rich growth conditions (28), suggesting a vital function of the proteasome under specific nutrient conditions. In another trichomonad, Tritrichomonas foetus, the proteasome inhibitor lactacystin A inhibits parasite growth (29).…”

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confidence: 99%

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20S Proteasome as a Drug Target in Trichomonas vaginalis

O’Donoghue

Bibo-Verdugo

Miyamoto

et al. 2019

Antimicrob Agents Chemother

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Trichomoniasis is a sexually transmitted disease with hundreds of millions of annual cases worldwide. Approved treatment options are limited to two related nitro-heterocyclic compounds, yet resistance to these drugs is an increasing concern. New antimicrobials against the causative agent, Trichomonas vaginalis, are urgently needed. We show here that clinically approved anticancer drugs that inhibit the proteasome, a large protease complex with a critical role in degrading intracellular proteins in eukaryotes, have submicromolar activity against the parasite in vitro and on-target activity against the enriched T. vaginalis proteasome in cell-free assays. Proteomic analysis confirmed that the parasite has all seven α and seven β subunits of the eukaryotic proteasome although they have only modest sequence identities, ranging from 28 to 52%, relative to the respective human proteasome subunits. A screen of proteasome inhibitors derived from a marine natural product, carmaphycin, revealed one derivative, carmaphycin-17, with greater activity against T. vaginalis than the reference drug metronidazole, the ability to overcome metronidazole resistance, and reduced human cytotoxicity compared to that of the anticancer proteasome inhibitors. The increased selectivity of carmaphycin-17 for T. vaginalis was related to its >5-fold greater potency against the β1 and β5 catalytic subunits of the T. vaginalis proteasome than against the human proteasome subunits. In a murine model of vaginal trichomonad infection, proteasome inhibitors eliminated or significantly reduced parasite burden upon topical treatment without any apparent adverse effects. Together, these findings validate the proteasome of T. vaginalis as a therapeutic target for development of a novel class of trichomonacidal agents.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

20S Proteasome as a Drug Target in Trichomonas vaginalis

O’Donoghue

Bibo-Verdugo

Miyamoto

et al. 2019

Antimicrob Agents Chemother

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“…All ATGs for the ATG8 conjugation system are identified in T. vaginalis, whereas ATGs for the ATG12 conjugation system are unclear. The parasite has two ATG8 isoforms [120,121]. In stark contrast, for G. lamblia all the main ATGs except for VPS34 and Vps15 homologs (also involved in non-autophagic processes) are missing, suggesting a complete absence of autophagy in this pathogen with very streamlined metabolic features (for instance, Giardia does not have classical lysosomes [122]).…”

Section: Function Of the Atgs In Entamoeba Sppmentioning

confidence: 99%

“…Expression of genes encoding TvATG4 and TvATG8a is upregulated by incubation in glucose-free medium [123]. In addition, TvATG8a-and TvATG8b-positive puncta increased upon glucose starvation, and the puncta formation was inhibited by treating with the VPS34 inhibitor wortmannin [120] and was accumulated by E-64d (a lysosomal protease inhibitor) treatment [121]. In glucose-rich conditions, autophagy was apparently stimulated by proteasome inhibition and led to the degradation of poly-ubiquitinated proteins [120].…”

Section: Function Of the Atgs In Metamonadamentioning

confidence: 99%

The Autophagy Machinery in Human-Parasitic Protists; Diverse Functions for Universally Conserved Proteins

Sakamoto

Nakada‐Tsukui

Besteiro

2021

Cells

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Autophagy is a eukaryotic cellular machinery that is able to degrade large intracellular components, including organelles, and plays a pivotal role in cellular homeostasis. Target materials are enclosed by a double membrane vesicle called autophagosome, whose formation is coordinated by autophagy-related proteins (ATGs). Studies of yeast and Metazoa have identified approximately 40 ATGs. Genome projects for unicellular eukaryotes revealed that some ATGs are conserved in all eukaryotic supergroups but others have arisen or were lost during evolution in some specific lineages. In spite of an apparent reduction in the ATG molecular machinery found in parasitic protists, it has become clear that ATGs play an important role in stage differentiation or organelle maintenance, sometimes with an original function that is unrelated to canonical degradative autophagy. In this review, we aim to briefly summarize the current state of knowledge in parasitic protists, in the light of the latest important findings from more canonical model organisms. Determining the roles of ATGs and the diversity of their functions in various lineages is an important challenge for understanding the evolutionary background of autophagy.

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“…Nevertheless, instances of autophagy-like processes, often supported by the presence of ATG8-positive structures, and their functional significance, have been reported for some parasitic protozoa. Examples include the encystation-associated autophagy-like process in Entamoeba [ 109 ], Acanthamoeba [ 110 ], and Naegleria [ 111 ], starvation-induced autophagy in T. vaginalis [ 112 , 113 ] and T. cruzi [ 114 ], glycosome turnover and damaged organelle removal by autophagy in Leishmania [ 115 ], and autophagy triggered by endoplasmic reticulum (ER) stress in T. gondii [ 116 ].…”

Section: Atg8 and Atg12: Moonlighting Autophagy Machinerymentioning

confidence: 99%

Ubiquitin-Like Modifiers: Emerging Regulators of Protozoan Parasites

Karpiyevich

Artavanis‐Tsakonas

2020

Biomolecules

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Post-translational protein regulation allows for fine-tuning of cellular functions and involves a wide range of modifications, including ubiquitin and ubiquitin-like modifiers (Ubls). The dynamic balance of Ubl conjugation and removal shapes the fates of target substrates, in turn modulating various cellular processes. The mechanistic aspects of Ubl pathways and their biological roles have been largely established in yeast, plants, and mammalian cells. However, these modifiers may be utilised differently in highly specialised and divergent organisms, such as parasitic protozoa. In this review, we explore how these parasites employ Ubls, in particular SUMO, NEDD8, ATG8, ATG12, URM1, and UFM1, to regulate their unconventional cellular physiology. We discuss emerging data that provide evidence of Ubl-mediated regulation of unique parasite-specific processes, as well as the distinctive features of Ubl pathways in parasitic protozoa. We also highlight the potential to leverage these essential regulators and their cognate enzymatic machinery for development of therapeutics to protect against the diseases caused by protozoan parasites.

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Potential role of autophagy in proteolysis in Trichomonas vaginalis

Cited by 13 publications

References 30 publications

20S Proteasome as a Drug Target in Trichomonas vaginalis

20S Proteasome as a Drug Target in Trichomonas vaginalis

The Autophagy Machinery in Human-Parasitic Protists; Diverse Functions for Universally Conserved Proteins

Ubiquitin-Like Modifiers: Emerging Regulators of Protozoan Parasites

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