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Translate regulation in trypanosomatids

Camila Oliveira, Paulo Costa Carvalho, Lysangela Ronalte Alves, Samuel Goldenberg
The regulation of gene expression in trypanosomatids occurs mainly at the post-transcriptional level. Despite the importance of this type of control in Trypanosoma cruzi, few RNA binding proteins have been characterized. The RRM domain (RNA Recognition Motif) is one of the most abundant domains found in RNA-binding proteins in higher eukaryotes. Proteins containing the RRM domain are involved in the majority of post-transcriptional processes regulating gene expression. In this work, we aimed to characterize the protein TcNRBD1 from T...
2016: PloS One
Baptiste Vergnes, Elodie Gazanion, Thomas Grentzinger
SIR2 proteins are NAD+-dependent deacetylases involved in epigenetic control of gene expression and metabolic regulation through post-translational modification of diverse target proteins. In pathogens, these enzymes are considered as attractive drug targets involved in key aspects of the infectious cycle. Leishmania infantum LiSIR2rp1 was among the first non-nuclear and essential SIR2 deacetylases described in eukaryotes. Here, we show that the two other LiSIR2rp2 and LiSIRrp3 paralogs are both located in mitochondria...
June 2016: Molecular and Biochemical Parasitology
María Albertina Romaniuk, Gabriela Cervini, Alejandro Cassola
Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening parasites affecting people in Sub-saharan Africa or in the Americas. In these parasites the classic view of regulation of transcription initiation to modulate the products of a given gene cannot be applied. This is due to the presence of transcription start sites that give rise to long polycistronic units that need to be processed costranscriptionally by trans-splicing and polyadenylation to give mature monocistronic mRNAs...
February 26, 2016: World Journal of Biological Chemistry
Lysangela Ronalte Alves, Samuel Goldenberg
RNA-binding proteins (RBPs) are key regulators of gene expression. There are several distinct families of RBPs and they are involved in the cellular response to environmental changes, cell differentiation and cell death. The RBPs can differentially combine with RNA molecules and form ribonucleoprotein (RNP) complexes, defining the function and fate of RNA molecules in the cell. RBPs display diverse domains that allow them to be categorized into distinct families. They play important roles in the cellular response to physiological stress, in cell differentiation, and, it is believed, in the cellular localization of certain mRNAs...
February 26, 2016: World Journal of Biological Chemistry
Mariana Bonilla, Erika Krull, Florencia Irigoín, Gustavo Salinas, Marcelo A Comini
The trace element selenium is found in polypeptides as selenocysteine, the 21(st) amino acid that is co-translationally inserted into proteins at a UGA codon. In proteins, selenocysteine usually plays a role as an efficient redox catalyst. Trypanosomatids previously examined harbor a full set of genes encoding the machinery needed for selenocysteine biosynthesis and incorporation into three selenoproteins: SelK, SelT and, the parasite-specific, Seltryp. We investigated the selenoproteome of kinetoplastid species in recently sequenced genomes and assessed the in vivo relevance of selenoproteins for African trypanosomes...
March 2016: Molecular and Biochemical Parasitology
Francisco Macías, Manuel Carlos López, M Carmen Thomas
BACKGROUND: Trypanosomatid genomes are highly colonized by non-LTR retroelements that make up to 5% of the nuclear genome. These elements are mainly accumulated in the strand switch regions (SSRs) where polycistronic transcription is initiated and have a 77 nt-long sequence--Pr77--at their 5' ends. L1Tc is the best represented retrotransposon in the Trypanosoma cruzi genome and is a potentially functional autonomous element that encodes its own retrotransposition machinery. The Pr77 of the T...
2016: BMC Genomics
Juan Manuel Polledo, Gabriela Cervini, María Albertina Romaniuk, Alejandro Cassola
RNA-binding proteins (RBPs) are involved in many aspects of mRNA metabolism such as splicing, nuclear export, translation, silencing, and decay. To cope with these tasks, these proteins use specialized domains such as the RNA recognition motif (RRM), the most abundant and widely spread RNA-binding domain. Although this domain was first described as a dedicated RNA-binding moiety, current evidence indicates these motifs can also engage in direct protein-protein interactions. Here, we discuss recent evidence describing the interaction between the RRM of the trypanosomatid RBP UBP1 and P22, the homolog of the human multifunctional protein P32/C1QBP...
February 2016: Current Genetics
Osvaldo P de Melo Neto, Tamara D C da Costa Lima, Camila C Xavier, Larissa M Nascimento, Tatiany P Romão, Ludmila A Assis, Mariana M C Pereira, Christian R S Reis, Barbara Papadopoulou
The eukaryotic initiation factor 4E (eIF4E) recognizes the mRNA cap structure and, together with eIF4G and eIF4A, form the eIF4F complex that regulates translation initiation in eukaryotes. In trypanosomatids, 2 eIF4E homologues (EIF4E3 and EIF4E4) have been shown to be part of eIF4F-like complexes with presumed roles in translation initiation. Both proteins possess unique N-terminal extensions, which can be targeted for phosphorylation. Here, we provide novel insights on the Leishmania infantum EIF4E4 function and regulation...
2015: RNA Biology
Shimi Meleppattu, Dikla Kamus-Elimeleh, Alexandra Zinoviev, Shahar Cohen-Mor, Irit Orr, Michal Shapira
Eukaryotic initiation factor 3 (eIF3) is a multi-protein complex and a key participant in the assembly of the translation initiation machinery. In mammals, eIF3 comprises 13 subunits, most of which are characterized by conserved structural domains. The trypanosomatid eIF3 subunits are poorly conserved. Here, we identify 12 subunits that comprise the Leishmania eIF3 complex (LeishIF3a-l) by combining bioinformatics with affinity purification and mass spectrometry analyses. These results highlight the strong association of LeishIF3 with LeishIF1, LeishIF2 and LeishIF5, suggesting the existence of a multi-factor complex...
July 27, 2015: Nucleic Acids Research
Pablo Smircich, Guillermo Eastman, Saloe Bispo, María Ana Duhagon, Eloise P Guerra-Slompo, Beatriz Garat, Samuel Goldenberg, David J Munroe, Bruno Dallagiovanna, Fabiola Holetz, Jose R Sotelo-Silveira
BACKGROUND: Due to the absence of transcription initiation regulation of protein coding genes transcribed by RNA polymerase II, posttranscriptional regulation is responsible for the majority of gene expression changes in trypanosomatids. Therefore, cataloging the abundance of mRNAs (transcriptome) and the level of their translation (translatome) is a key step to understand control of gene expression in these organisms. RESULTS: Here we assess the extent of regulation of the transcriptome and the translatome in the Chagas disease causing agent, Trypanosoma cruzi, in both the non-infective (epimastigote) and infective (metacyclic trypomastigote) insect's life stages using RNA-seq and ribosome profiling...
2015: BMC Genomics
Lysangela Ronalte Alves, Camila Oliveira, Samuel Goldenberg
BACKGROUND: Regulation of gene expression in trypanosomatids is mainly posttranscriptional. Tight regulation of mRNA stability and access to polysomes allows Trypanosoma cruzi to adapt to different environmental conditions during its life cycle. Posttranscriptional regulation requires association between mRNAs and specific proteins to form mRNP complexes. Proteins that lack a canonical RNA-binding domain, such as eukaryotic elongation factor-1α (EF-1α), may also associate with mRNPs...
2015: BMC Microbiology
Gerald F Späth, Sima Drini, Najma Rachidi
Across bacterial, archaeal and eukaryotic kingdoms, heat shock proteins (HSPs) are defined as a class of highly conserved chaperone proteins that are rapidly induced in response to temperature increase through dedicated heat shock transcription factors. While this transcriptional response governs cellular adaptation of fungal, plant and animal cells to thermic shock and other forms of stress, early-branching eukaryotes of the kinetoplastid order, including trypanosomatid parasites, lack classical mechanisms of transcriptional regulation and show largely constitutive expression of HSPs, thus raising important questions on the function of HSPs in the absence of stress and the regulation of their chaperone activity in response to environmental adversity...
May 2015: Cellular Microbiology
Pedro J Alcolea, Ana Alonso, Francisco García-Tabares, Alfredo Toraño, Vicente Larraga
The life cycle of the trypanosomatid Crithidia fasciculata is monogenetic, as the unique hosts of these parasites are different species of culicids. The comparison of these non-pathogenic microorganisms evolutionary close to other species of trypanosomatids that develop digenetic life cycles and cause chronic severe sickness to millions of people worldwide is of outstanding interest. A ground-breaking analysis of differential protein abundance in Crithidia fasciculata is reported herein. The comparison of the outcome with previous gene expression profiling studies developed in the related human pathogens of the genus Leishmania has revealed substantial differences between the motile stages of these closely related organisms in abundance of proteins involved in catabolism, redox homeostasis, intracellular signalling, and gene expression regulation...
2014: PloS One
Juciane Vaz Rêgo, Ana Paula Duarte, Daniel Barbosa Liarte, Francirlene de Carvalho Sousa, Humberto Medeiros Barreto, Jacqueline Bua, Alvaro José Romanha, Gandhi Rádis-Baptista, Silvane Maria Fonseca Murta
Cyclophilin (CyP), a peptidyl-prolyl cis/trans isomerase, is a key molecule with diverse biological functions that include roles in molecular chaperoning, stress response, immune modulation, and signal transduction. In this respect, CyP could serve as a potential drug target in disease-causing parasites. Previous studies employing proteomics techniques have shown that the TcCyP19 isoform was more abundant in a benznidazole (BZ)-resistant Trypanosoma cruzi population than in its susceptible counterpart. In this study, TcCyP19 has been characterized in BZ-susceptible and BZ-resistant T...
January 2015: Experimental Parasitology
Fernanda A H Batista, Glessler S Almeida, Thiago V Seraphim, Kelly P Silva, Silvane M F Murta, Leandro R S Barbosa, Júlio C Borges
The small acidic protein called p23 acts as a co-chaperone for heat-shock protein of 90 kDa (Hsp90) during its ATPase cycle. p23 proteins inhibit Hsp90 ATPase activity and show intrinsic chaperone activity. A search for p23 in protozoa, especially trypanosomatids, led us to identify two putative proteins in the Leishmania braziliensis genome that share approximately 30% identity with each other and with the human p23. To understand the presence of two p23 isoforms in trypanosomatids, we obtained the recombinant p23 proteins of L...
January 2015: FEBS Journal
Subhankar Dolai, Subrata Adak
Perturbation of endoplasmic reticulum (ER) homeostasis can lead to an accumulation of misfolded proteins within the ER lumen causing initiation of ER stress. To reestablish homeostasis and mitigate the stress, a series of adaptive intracellular signaling pathways termed the unfolded protein response (UPR) are activated. ER stress is of considerable interest to parasitologists because it takes place in parasites subjected to adverse environmental conditions. During a digenetic lifestyle, Leishmania parasites encounter and adapt to harsh environmental conditions that provide potential triggers of ER stress...
October 2014: Molecular and Biochemical Parasitology
Esteban D Erben, Abeer Fadda, Smiths Lueong, Jörg D Hoheisel, Christine Clayton
In trypanosomatids, gene expression is regulated mainly by post-transcriptional mechanisms, which affect mRNA processing, translation and degradation. Currently, our understanding of factors that regulate either mRNA stability or translation is rather limited. We know that often, the regulators are proteins that bind to the 3'-untranslated region; they presumably interact with ribonucleases and translation factors. However, very few such proteins have been characterized in any detail. Here we describe a genome-wide screen to find proteins implicated in post-transcriptional regulation in Trypanosoma brucei...
June 2014: PLoS Pathogens
Fabricio K Marchini, Lyris Martins Franco de Godoy, Michel Batista, Fernanda G Kugeratski, Marco A Krieger
The identification and localization of protein phosphorylation sites provide clues to what proteins or pathways might be activated in a given condition, helping to improve our understanding about signaling networks. Advances in strategies for enrichment of phosphorylated peptides/proteins, mass spectrometry (MS) instrumentation, and specific MS techniques for identification and quantification of post-translational modifications have allowed for large-scale mapping of phosphorylation sites, promoting the field of phosphoproteomics...
2014: Sub-cellular Biochemistry
Jose Batista de Jesus, Camila Mesquita-Rodrigues, Patricia Cuervo
Leishmania spp. are digenetic parasites which cause a broad spectrum of fatal diseases in humans. These parasites, as well as the other trypanosomatid, regulate gene expression at the post-transcriptional and post-translational levels, so that a poor correlation is observed between mRNA content and translated proteins. The completion of the genomic sequencing of several Leishmania species has enormous relevance to the study of the leishmaniasis pathogenesis. The combination of the available genomic resources of these parasites with powerful high-throughput proteomic analysis has shed light on various aspects of Leishmania biology as well as on the mechanisms underlying the disease...
2014: Sub-cellular Biochemistry
Mainá Bitar, Mariana Boroni, Andréa M Macedo, Carlos R Machado, Glória R Franco
THE SPLICED LEADER (SL) IS A GENE THAT GENERATES A FUNCTIONAL NCRNA THAT IS COMPOSED OF TWO REGIONS: an intronic region of unknown function (SLi) and an exonic region (SLe), which is transferred to the 5' end of independent transcripts yielding mature mRNAs, in a process known as spliced leader trans-splicing (SLTS). The best described function for SLTS is to solve polycistronic transcripts into monocistronic units, specifically in Trypanosomatids. In other metazoans, it is speculated that the SLe addition could lead to increased mRNA stability, differential recruitment of the translational machinery, modification of the 5' region or a combination of these effects...
2013: Frontiers in Genetics
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