A 43-Nucleotide U-rich Element in 3′-Untranslated Region of Large Number of Trypanosoma cruzi Transcripts Is Important for mRNA Abundance in Intracellular Amastigotes

Li, Zhu Hong; Gaudenzi, Javier G. De; Álvarez, Vanina E.; Mendiondo, Nicolás; Wang, Haiming; Kissinger, Jessica C.; Frasch, Alberto C.C.; Docampo, Roberto

doi:10.1074/jbc.m111.338699

Cited by 26 publications

(23 citation statements)

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“…In the past few years several reports provided evidence indicating that trypanosomal transcripts are organized as post-transcriptional regulons (Archer et al, 2009; Das et al, 2012; Estevez, 2008; Guerra-Slompo et al, 2012; Mayho et al, 2006; Noe, De Gaudenzi & Frasch, 2008). Furthermore, several RBPs have also been shown to interact with a subset of stage-specific mRNAs, suggesting the presence of developmental regulons (Dallagiovanna et al, 2008; Li et al, 2012; Mörking et al, 2012; Walrad et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of 3′-untranslated regions supports the existence of post-transcriptional regulons controlling gene expression in trypanosomes

Gaudenzi

Carmona

Agüero

et al. 2013

PeerJ

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In eukaryotic cells, a group of messenger ribonucleic acids (mRNAs) encoding functionally interrelated proteins together with the trans-acting factors that coordinately modulate their expression is termed a post-transcriptional regulon, due to their partial analogy to a prokaryotic polycistron. This mRNA clustering is organized by sequence-specific RNA-binding proteins (RBPs) that bind cis-regulatory elements in the noncoding regions of genes, and mediates the synchronized control of their fate. These recognition motifs are often characterized by conserved sequences and/or RNA structures, and it is likely that various classes of cis-elements remain undiscovered. Current evidence suggests that RNA regulons govern gene expression in trypanosomes, unicellular parasites which mainly use post-transcriptional mechanisms to control protein synthesis. In this study, we used motif discovery tools to test whether groups of functionally related trypanosomatid genes contain a common cis-regulatory element. We obtained conserved structured RNA motifs statistically enriched in the noncoding region of 38 out of 53 groups of metabolically related transcripts in comparison with a random control. These motifs have a hairpin loop structure, a preferred sense orientation and are located in close proximity to the open reading frames. We found that 15 out of these 38 groups represent unique motifs in which most 3′-UTR signature elements were group-specific. Two extensively studied Trypanosoma cruzi RBPs, TcUBP1 and TcRBP3 were found associated with a few candidate RNA regulons. Interestingly, 13 motifs showed a strong correlation with clusters of developmentally co-expressed genes and six RNA elements were enriched in gene clusters affected after hyperosmotic stress. Here we report a systematic genome-wide in silico screen to search for novel RNA-binding sites in transcripts, and describe an organized network of several coordinately regulated cohorts of mRNAs in T. cruzi. Moreover, we found that structured RNA elements are also conserved in other human pathogens. These results support a model of regulation of gene expression by multiple post-transcriptional regulons in trypanosomes.

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Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of 3′-untranslated regions supports the existence of post-transcriptional regulons controlling gene expression in trypanosomes

Gaudenzi

Carmona

Agüero

et al. 2013

PeerJ

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“…In T. cruzi, the role of AREs in the 3 0 UTR of TcSMUG mRNA mediating developmental regulation has been suggested [21,22]. Besides, a 3 0 UTR 43-nt U rich element, which also includes an ARE core pentamer, has been involved in the modulation of mRNA abundance in the intracellular amastigote stage [23]. However, no significant similarity of the tcrbp19 3 0 UTR to this 43-nt U element was found.…”

Section: The Tcrbp19 3 0 Utr Down-regulates Reporter Gene Transcriptsmentioning

confidence: 99%

Evidence for a negative feedback control mediated by the 3′ untranslated region assuring the low expression level of the RNA binding protein TcRBP19 in T. cruzi epimastigotes

Pérez-Díaz

Pastro

Smircich

et al. 2013

Biochemical and Biophysical Research Communications

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Because of their relevant role in the post-transcriptional regulation of the expression of a multitude of genes, RNA-binding proteins (RBPs) need to be accurately regulated in response to environmental signals in terms of quantity, functionality and localization. Transcriptional, post-transcriptional and post-translational steps have all been involved in this tight control. We have previously identified a Trypanosoma cruzi RBP, named TcRBP19, which can barely be detected at the replicative intracellular amastigote stage of the mammalian host. Even though protein coding genes are typically transcribed constitutively in trypanosomes, TcRBP19 protein is undetectable at the epimastigote stage. Here, we show that this protein expression pattern follows the steady-state of its mRNA. Using a T. cruzi reporter gene approach, we could establish a role for the 3' UTR of the tcrbp19 mRNA in transcript down-regulation at the epimastigote stage. In addition, the binding of the TcRBP19 protein to its encoding mRNA was revealed by in vitro pull down followed by qRT-PCR and confirmed by CLIP assays. Furthermore, we found that forced over-expression of TcRBP19 in T. cruzi epimastigotes decreased the stability of the endogenous tcrbp19 mRNA. These results support a negative feedback control of TcRBP19 to help maintain its very low concentration of TcRBP19 in the epimastigote stage. To our knowledge, this is the first RBP reported in trypanosomatids capable of negatively regulating its own mRNA. The mechanism revealed here adds to our limited but growing number of examples of negative mRNA autoregulation in the control of gene expression.

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“…Leishmania harbors a large family of extinct retroposons, SIDERs (Short Interspersed DEgenerated Retroposons), that are widely distributed within the 3′ UTRs of unrelated transcripts and participate in posttranscriptional regulation (Bringaud et al, 2007;Smith et al, 2009;Muller et al, 2010). Uridine-rich elements (UREs), initially reported as destabilization factors in protooncogenes and cytokine mRNAs in mammalian cells (Chen and Shyu, 1995;Schoenberg and Maquat, 2012), and URE-binding proteins have been described in T. brucei (Hotz et al, 1997;Quijada et al, 2002;Mayho et al, 2006) and T. cruzi (Di Noia et al, 2000;Rodrigues et al, 2010;Li et al, 2012) and more recently in Leishmania (Haile et al, 2008). Other non-categorized elements within 3′ UTRs involved in stage-specific mRNA regulation, such as the PRE element AUGUAnAGUn are responsible for the degradation of transcripts encoding paraflagellar rod subunits or an antigenic protein in L. mexicana (Mishra et al, 2003;Holzer et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

An Alba‐domain protein contributes to the stage‐regulated stability of amastin transcripts in Leishmania

Dupé

Dumas

Papadopoulou

2013

Molecular Microbiology

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SummaryLeishmania infantum promastigotes differentiate into amastigote forms within the phagolysosome of mammalian macrophages causing visceral leishmaniasis. Delta-amastins belong to a multigenic surface protein family of potential virulence factors that are specifically expressed in the amastigote life cycle stage through distinct regulatory elements in the 3′ UTR controlling either mRNA stability or translation. Here, we provide novel insights on trans-acting factors regulating amastin developmental gene expression. Using RNA affinity chromatography with a 300 nt regulatory region within the amastin 3′ UTR as bait, we identified an Alba-domain protein of 25 kDa (LiAlba20) as a specific amastin mRNA-binding partner. Genomic depletion of LiAlba20 results in amastin mRNA destabilization specifically in amastigotes, supporting a role of LiAlba20 in amastin gene regulation. As shown by comparative DNA microarray analysis, several delta-amastin transcripts but also other known developmentally regulated transcripts were downregulated in LiAlba20−/− knockout parasites. Inactivation of the second Alba-domain gene, LiAlba13, does not seem to affect amastin mRNA stability in either life stage of the parasite. These data indicate an important role of Alba-domain proteins in the regulation of Leishmania differentially expressed transcripts and open a new field of investigation for better understanding mechanisms contributing to post-transcriptional control in these parasites.

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A 43-Nucleotide U-rich Element in 3′-Untranslated Region of Large Number of Trypanosoma cruzi Transcripts Is Important for mRNA Abundance in Intracellular Amastigotes

Cited by 26 publications

References 50 publications

Genome-wide analysis of 3′-untranslated regions supports the existence of post-transcriptional regulons controlling gene expression in trypanosomes

Genome-wide analysis of 3′-untranslated regions supports the existence of post-transcriptional regulons controlling gene expression in trypanosomes

Evidence for a negative feedback control mediated by the 3′ untranslated region assuring the low expression level of the RNA binding protein TcRBP19 in T. cruzi epimastigotes

An Alba‐domain protein contributes to the stage‐regulated stability of amastin transcripts in Leishmania

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