tRNA Biology in Trypanosomes

Shikha, Shikha; Brogli, Rebecca; Schneider, André; Polacek, Norbert

doi:10.2533/chimia.2019.395

Cited by 12 publications

(8 citation statements)

References 83 publications

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“…Moreover, tRNAs appear to be imported as fully processed molecules (11,12). The exclusive reliance on mitochondrial tRNA import has initiated a more general interest in trypanosomal tRNA biology (1). Aminoacyl-tRNA synthetases (aaRSs) have been studied extensively and it was shown that, likely due to mitochondrial tRNA import, most but interestingly not all aaRSs are dually targeted to the cytosol and the mitochondrion (3,(13)(14)(15).…”

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The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria

Shikha

Schneider

2020

Journal of Biological Chemistry

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tRNAs universally carry a CCA nucleotide triplet at their 3′-ends. In eukaryotes, the CCA is added post-transcriptionally by the CCA-adding enzyme (CAE). The mitochondrion of the parasitic protozoan Trypanosoma brucei lacks tRNA genes and therefore imports all of its tRNAs from the cytosol. This has generated interest in the tRNA modifications and their distribution in this organism, including how CCA is added to tRNAs. Here, using a BLAST search for genes encoding putative CAE proteins in T. brucei, we identified a single ORF, Tb927.9.8780, as a potential candidate. Knockdown of this putative protein, termed TbCAE, resulted in the accumulation of truncated tRNAs, abolished translation, and inhibited both total and mitochondrial CCA-adding activities, indicating that TbCAE is located both in the cytosol and mitochondrion. However, mitochondrially localized tRNAs were much less affected by the TbCAE ablation than the other tRNAs. Complementation assays revealed that the N-terminal 10 amino acids of TbCAE are dispensable for its activity and mitochondrial localization and that deletion of 10 further amino acids abolishes both. A growth arrest caused by the TbCAE knockdown was rescued by the expression of the cytosolic isoform of yeast CAE, even though it was not imported into mitochondria. This finding indicated that the yeast enzyme complements the essential function of TbCAE by adding CCA to the primary tRNA transcripts. Of note, ablation of the mitochondrial TbCAE activity, which likely has a repair function, only marginally affected growth.

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The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria

Shikha

Schneider

2020

Journal of Biological Chemistry

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“…As such it might represent a novel pathway that supports host-parasite interactions and sustains infection. In this context, complementing the pool of tRNAs transcribed by the parasite with the import of specific exogenous/host tRNAs could play a punctual role during the developmental cycle, either by promoting protein synthesis at specific stages or by enabling unrelated signaling processes such as those reviewed in ( 47 , 48 , 49 ). The absence of other examples of import of exogenous tRNAs beyond the Plasmodium genus complicates its characterization but also offers new opportunities.…”

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Identification of host tRNAs preferentially recognized by the Plasmodium surface protein tRip

Cela

Théobald-Dietrich

Rudinger-Thirion

et al. 2021

Nucleic Acids Research

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Malaria is a life-threatening and devastating parasitic disease. Our previous work showed that parasite development requires the import of exogenous transfer RNAs (tRNAs), which represents a novel and unique form of host–pathogen interaction, as well as a potentially druggable target. This import is mediated by tRip (tRNA import protein), a membrane protein located on the parasite surface. tRip displays an extracellular domain homologous to the well-characterized OB-fold tRNA-binding domain, a structural motif known to indiscriminately interact with tRNAs. We used MIST (Microarray Identification of Shifted tRNAs), a previously established in vitro approach, to systematically assess the specificity of complexes between native Homo sapiens tRNAs and recombinant Plasmodium falciparum tRip. We demonstrate that tRip unexpectedly binds to host tRNAs with a wide range of affinities, suggesting that only a small subset of human tRNAs is preferentially imported into the parasite. In particular, we show with in vitro transcribed constructs that tRip does not bind specific tRNAs solely based on their primary sequence, hinting that post-transcriptional modifications modulate the formation of our host/parasite molecular complex. Finally, we discuss the potential utilization of the most efficient tRip ligands for the translation of the parasite's genetic information.

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“…Also, a numerical “2” is appended to the mitochondrial version of the synthetase, for example, in aspartyl tRNA synthetase, the cytosolic form is abbreviated as DRS1 and the mitochondrial form as DRS2. It is noteworthy that unlike other eukaryotes that possess at least two genes for most of the cytosolic and mitochondrial aaRSs, the trypanosomatids encode only one gene except for a few, such as AspRS, TrpRS, and LysRS. , In trypanosomatids, 26 aaRSs have been recognized . In reference to Trypanosoma, a study revealed that alternate trans-splicing of an immature RNA results in formation of isoforms, the one with mitochondria targeting sequence (MTS) is directed toward mitochondria while the one devoid of MTS is retained within cytosol .…”

Section: Aminoacyl Trna Synthetases As Drug Targetmentioning

confidence: 99%

Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

Nasim

Qureshi

2023

ACS Omega

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The ensemble of aminoacyl tRNA synthetases is regarded as a key component of the protein translation machinery. With the progressive increase in structure-based studies on tRNA synthetase-ligand complexes, the detailed picture of these enzymes is becoming clear. Having known their critical role in deciphering the genetic code in a living system, they have always been chosen as one of the important targets for development of antimicrobial drugs. Later on, the role of aminoacyl tRNA synthetases (aaRSs) on the survivability of trypanosomatids has also been validated. It became evident through several gene knockout studies that targeting even one of these enzymes affected parasitic growth drastically. Such successful studies have inspired researchers to search for inhibitors that could specifically target trypanosomal aaRSs, and their never-ending efforts have provided fruitful results. Taking all such studies into consideration, these macromolecules of prime importance deserve further investigation for the development of drugs that cure spectrum of infections caused by trypanosomatids. In this review, we have compiled advancements of over a decade that have taken place in the pursuit of devising drugs by using trypanosomatid aaRSs as a major target of interest. Several of these inhibitors work on an exemplary low concentration range without posing any threat to the mammalian cells which is a very critical aspect of the drug discovery process. Advancements have been made in terms of using structural biology as an important tool to analyze the architecture of the trypanosomatids aaRSs and concoction of inhibitors with augmented specificities toward their targets. Some of the inhibitors that have been tested on other parasites successfully but their efficacy has so far not been validated against these trypanosomatids have also been appended.

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tRNA Biology in Trypanosomes

Cited by 12 publications

References 83 publications

The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria

The single CCA-adding enzyme of T. brucei has distinct functions in the cytosol and in mitochondria

Identification of host tRNAs preferentially recognized by the Plasmodium surface protein tRip

Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

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