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Translate regulation in trypanosomatids

Céline Ronin, David Mendes Costa, Joana Tavares, Joana Faria, Fabrice Ciesielski, Paola Ciapetti, Terry K Smith, Jane MacDougall, Anabela Cordeiro-da-Silva, Iain K Pemberton
The de novo crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSir2rp1) has been solved at 1.99Å in complex with an acetyl-lysine peptide substrate. The structure is broadly commensurate with Hst2/SIRT2 proteins of yeast and human origin, reproducing many of the structural features common to these sirtuin deacetylases, including the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions. The two domains are linked via a cofactor binding loop ordered in open conformation...
2018: PloS One
Eden R Freire, Danielle M N Moura, Maria J R Bezerra, Camila C Xavier, Mariana C Morais-Sobral, Ajay A Vashisht, Antonio M Rezende, James A Wohlschlegel, Nancy R Sturm, Osvaldo P de Melo Neto, David A Campbell
Trypanosomatids are parasitic protozoans characterized by several unique structural and metabolic processes that include exquisite mechanisms associated with gene expression and regulation. During the initiation of protein synthesis, for instance, mRNA selection for translation seems to be mediated by different eIF4F-like complexes, which may play a significant role in parasite adaptation to different hosts. In eukaryotes, the heterotrimeric eIF4F complex (formed by eIF4E, eIF4G, and eIF4A) mediates mRNA recognition and ribosome binding and participates in various translation regulatory events...
December 29, 2017: Current Genetics
Pravin K Jha, Mohd Imran Khan, Anshul Mishra, Pradeep Das, Kislay K Sinha
Histone post-translational modifications (PTMs) such as acetylation and methylation are known to affect chromatin higher order structures. Primary targets of these modifications include basic residues present at N-terminus tail region of core histones. Four histone acetyltransferase (HAT) genes have been identified in trypanosomatids. HAT1, HAT3 and HAT4 of Leishmania donovani have been partially characterized. However, there is no report about HAT2 of Leishmania donovani. Lysine residues present on the N-terminal tail of Leishmania donovani histone H4 are conserved in other trypanosomatids and humans...
2017: PloS One
Camila Oliveira, Helisson Faoro, Lysangela Ronalte Alves, Samuel Goldenberg
RNA-binding proteins (RBPs) have important functions in the regulation of gene expression. RBPs play key roles in post-transcriptional processes in all eukaryotes, such as splicing regulation, mRNA transport and modulation of mRNA translation and decay. RBPs assemble into different mRNA-protein complexes, which form messenger ribonucleoprotein complexes (mRNPs). Gene expression regulation in trypanosomatids occurs mainly at the post-transcriptional level and RBPs play a key role in all processes. However, the functional characterization of RBPs in Trypanosoma cruzi has been impaired due to the lack of reliable reverse genetic manipulation tools...
January 2017: Genetics and Molecular Biology
Devki Nandan, Sneha A Thomas, Anne Nguyen, Kyung-Mee Moon, Leonard J Foster, Neil E Reiner
Leishmania are unicellular eukaryotes responsible for leishmaniasis in humans. Like other trypanosomatids, leishmania regulate protein coding gene expression almost exclusively at the post-transcriptional level with the help of RNA binding proteins (RBPs). Due to the presence of polycystronic transcription units, leishmania do not regulate RNA polymerase II-dependent transcription initiation. Recent evidence suggests that the main control points in gene expression are mRNA degradation and translation. Protein-RNA interactions are involved in every aspect of RNA biology, such as mRNA splicing, polyadenylation, localization, degradation, and translation...
2017: PloS One
Gisele F A Picchi, Vanessa Zulkievicz, Marco A Krieger, Nilson T Zanchin, Samuel Goldenberg, Lyris M F de Godoy
Chagas disease, caused by Trypanosoma cruzi, still affects millions of people around the world. No vaccines nor treatment for chronic Chagas disease are available, and chemotherapy for the acute phase is hindered by limited efficacy and severe side effects. The processes by which the parasite acquires infectivity and survives in different hosts involve tight regulation of gene expression, mainly post-transcriptionally. Nevertheless, chromatin structure/organization of trypanosomatids is similar to other eukaryotes, including histone variants and post-translational modifications...
March 3, 2017: Journal of Proteome Research
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...
February 9, 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
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