Control Of Protein Translation Research Articles

The hidden nature of protein translational control by diphthamide: the secrets under the leather.

The protein translation elongation factor eEF2 undergoes a unique posttranslational modification called diphthamidation. eEF2 is an essential factor in protein translation, and the diphthamide modification has been a famous target of the diphtheria toxin for a long time. On the other hand, the physiological function of this rare modification in vivo remains unknown. Recent studies have suggested that diphthamide has specific functions for the cellular stress response and active proliferation. In this review, we summarize the history and findings of diphthamide obtained to date and discuss the possibility of a specific function for diphthamide in regulating protein translation.

Queuosine‐modified tRNAs confer nutritional control of protein translation

Global protein translation as well as translation at the codon level can be regulated by tRNA modifications. In eukaryotes, levels of tRNA queuosinylation reflect the bioavailability of the precursor queuine, which is salvaged from the diet and gut microbiota. We show here that nutritionally determined Q‐tRNA levels promote Dnmt2‐mediated methylation of tRNA Asp and control translational speed of Q‐decoded codons as well as at near‐cognate codons. Deregulation of translation upon queuine depletion results in unfolded proteins that trigger endoplasmic reticulum stress and activation of the unfolded protein response, both in cultured human cell lines and in germ‐free mice fed with a queuosine‐deficient diet. Taken together, our findings comprehensively resolve the role of this anticodon tRNA modification in the context of native protein translation and describe a novel mechanism that links nutritionally determined modification levels to effective polypeptide synthesis and cellular homeostasis.

ABCF3 regulates the expression of aquaporin genes and endoplasmic reticulum stress-related genes in Arabidopsis

The ATP-binding cassette (ABC) F/GCN (general control non-derepressible) subfamily is a group of soluble ABC proteins that has two nucleotide binding domains (NBDs) but no transmembrane domains (TMDs). Previous study has indicated that ABCF3, also called GCN20/SCORD5, is involved in stress-associated protein translation control and defense responses to bacterial infection. Here, we show that ABCF3 regulates H2O2 uptake and endoplasmic reticulum (ER) stress responses in Arabidopsis. ABCF3 expressed mainly in leaves, stems, root tips, seeds, and anther. Analysis of abcf3 mutants and transgenic overexpressors (OX) of ABCF3 indicates that ABCF3 regulates H2O2 uptake. qRT-PCR analysis indicated that ABCF3 affects the expression of several aquaporin genes that were involved in H2O2 uptake in plants. In addition, abcf3 mutants exhibited enhanced sensitivity to ER stress and amino acid deprivation when challenged with ER stress inducers tunicamycin and amino acid synthesis inhibitor chlorsulfuron compared to wild type. Overexpression of AtABCF3 increases, whereas, abcf3 mutants depress the expression of ER stress-related genes. Taken together, these results indicated that ABCF3 regulates stress response by modulating aquaporin gene expression and ER stress responses.

Protein Synthesis and Translational Control: A Historical Perspective.

Protein synthesis and its regulation are central to all known forms of life and impinge on biological arenas as varied as agriculture, biotechnology, and medicine. Otherwise known as translation and translational control, these processes have been investigated with increasing intensity since the middle of the 20th century, and in increasing depth with advances in molecular and cell biology. We review the origins of the field, focusing on the underlying concepts and early studies of the cellular machinery and mechanisms involved. We highlight key discoveries and events on a timeline, consider areas where current research has engendered new ideas, and conclude with some speculation on future directions for the field.

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice.

Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson’s disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout (KO) of Lrrk2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of Lrrk2 KO mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 KO kidneys. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutation. Using cultured epithelial kidney cells, we replicated the accumulation of lysosomal proteases and demonstrated changes in subcellular distribution of the cation-independent mannose-6-phosphate receptor. These results show that loss of LRRK2 leads to co-ordinated responses in protein translation and trafficking and argue against a dominant negative role for the G2019S mutation.

Translation Control by p53.

The translation of mRNAs plays a critical role in the regulation of gene expression and therefore, in the regulation of cell proliferation, differentiation and apoptosis. Unrestricted initiation of translation causes malignant transformation and plays a key role in the maintenance and progression of cancers. Translation initiation is regulated by the ternary complex and the eukaryotic initiation factor 4F (eIF4F) complex. The p53 tumor suppressor protein is the most well studied mammalian transcription factor that mediates a variety of anti-proliferative processes. Post-transcriptional mechanisms of gene expression in general and those of translation in particular play a major role in shaping the protein composition of the cell. The p53 protein regulates transcription and controls eIF4F, the ternary complex and the synthesis of ribosomal components, including the down-regulation of rRNA genes. In summary, the induction of p53 regulates protein synthesis and translational control to inhibit cell growth.

Mathematical Modeling of Mammalian Target of Rapamycin following Leucine Ingestion

The mammalian target of rapamycin complex 1 (mTORC1) is a regulatory protein for several cell processes and is critical in the control of muscle protein synthesis and hence muscle size. Its activity is primarily regulated by nutrition (i.e., protein) and growth factors (i.e., insulin); however, how the whole-body dynamics of these factors translate into protein translational signaling in skeletal muscle cells is poorly understood. PURPOSE: The purpose of this study was to develop and analyze a simple mathematical model of the signaling controlling protein translation in human skeletal muscle following leucine ingestion. METHODS: The model was expressed as a system of ordinary differential equations (ODEs) incorporating the signaling proteins involved in the control of protein translation (e.g., IR/PI3K/AKT/mTOR axis). Intracellular biochemical reactions were represented by mass-action kinetics. We constructed the model by modifying amalgamated published models of mTOR signalling [Pezze et al. (2012) Sci Signal] and skeletal-muscle leucine kinetics [Tessari et al. (1995) Am J Physiol]. The Pezze model was specific to HeLa cells, so we calibrated the kinetic parameters using signaling data from human skeletal muscle following leucine ingestion. The ODEs were solved using the ODE23s solver in MATLAB. RESULTS: The model outputs qualitatively agreed with published time-course data for plasma leucine, plasma insulin, and phosphorylation of AktS473, mTORC1S2448, and p70S6KT389 following the ingestion of a single leucine bolus or multiple, pulsatile leucine doses. Parameter sensitivity analysis determined that mTORC1 activity was most sensitive to total mTORC1 concentration and highly sensitive to the rate of leucine transamination to alpha-ketoisocaproate. CONCLUSION: Our model represents a working quantitative hypothesis of the dynamics of protein translational control in skeletal muscle by nutritional and hormonal factors.

Update of thermotolerant genes essential for survival at a critical high temperature in Escherichia coli.

Previous screening of a single-gene knockout library consisting of 3,908 disrupted-mutant strains allowed us to identify 51 thermotolerant genes that are essential for survival at a critical high temperature (CHT) in Escherichia coli [Murata M, Fujimoto H, Nishimura K, Charoensuk K, Nagamitsu H, Raina S, Kosaka T, Oshima T, Ogasawara N, Yamada M (2011) PLoS ONE 6: e20063]. In this study, we identified another 21 thermotolerant genes. E. coli thus has 72 thermotolerant genes in total. The genes are classified into 8 groups: genes for energy metabolism, outer membrane organization, DNA double-strand break repair, tRNA modification, protein quality control, translation control, cell division and transporters. This classification and physiological analysis indicate the existence of fundamental strategies for survival at a CHT, which seems to exclude most of the heat shock responses.

Ginsenoside Rh2 inhibits prostate cancer cell growth through suppression of microRNA‐4295 that activates CDKN1A

Ginsenoside Rh2 (GRh2) has demonstrative therapeutic effects on a variety of diseases, including some tumours. However, the effects of GRh2 on prostate cancer (PC) cell growth remain unknown, and were, thus, addressed in the present study. PC3 and DU145 PC cell lines were exposed to GRh2. Cell proliferation was assessed in an MTT assay and by BrdU incorporation. Apoptosis of the cells were assessed by TUNEL staining. Total RNA was assessed by RT-qPCR. Protein levels were assessed by Western blotting. Bioinformatics and dual luciferase reporter assay were applied to determine the functional binding of miRNA to mRNA of target gene. GRh2 dose-dependently decreased PC cell proliferation, but did not alter cell apoptosis. Mechanistically, GRh2 dose-dependently increased the protein, but not mRNA of a cell-cycle suppressor CDKN1A in PC cells, suggesting the presence of microRNA (miRNA)-mediated protein translation control of CDKN1A by GRh2. In all candidate miRNAs that bind to 3'-UTR of CDKN1A, miR-4295 was specifically found to be suppressed dose-dependently by GRh2 in PC cells. Moreover, miR-4295 bound CDKN1A to suppress its protein translation. Furthermore, cell proliferation in PC cells that overexpressed miR-4295 did not alter in response to GRh2. GRh2 may inhibit PC cell growth through suppression of microRNA-4295 that activates CDKN1A.

Association of Gnrhr mRNA With the Stem Cell Determinant Musashi: A Mechanism for Leptin-Mediated Modulation of GnRHR Expression.

The cyclic expression of pituitary gonadotropin-releasing hormone receptors (GnRHRs) may be an important checkpoint for leptin regulatory signals. Gonadotrope Lepr-null mice have reduced GnRHR levels, suggesting these receptors may be leptin targets. To determine if leptin stimulated GnRHR directly, primary pituitary cultures or pieces were exposed to 1 to 100 nM leptin. Leptin increased GnRHR protein levels and the percentages of gonadotropes that bound biotinylated analogs of gonadotropin-releasing hormone (bio-GnRH) but had no effect on Gnrhr messenger RNA (mRNA). An in silico analysis revealed three consensus Musashi (MSI) binding elements (MBEs) for this translational control protein in the 3' untranslated region (UTR) of Gnrhr mRNA. Several experiments determined that these Gnrhr mRNA MBE were active: (1) RNA electrophoretic mobility shift assay analyses showed that MSI1 specifically bound Gnrhr mRNA 3'-UTR; (2) RNA immunoprecipitation of pituitary fractions with MSI1 antibody pulled down a complex enriched in endogenous MSI protein and endogenous Gnrhr mRNA; and (3) fluorescence reporter assays showed that MSI1 repressed translation of the reporter coupled to the Gnrhr 3'-UTR. In vitro, leptin stimulation of pituitary pieces reduced Msi1 mRNA in female pituitaries, and leptin stimulation of pituitary cultures reduced MSI1 proteins selectively in gonadotropes identified by binding to bio-GnRH. These findings show that leptin's direct stimulatory actions on gonadotrope GnRHR correlate with a direct inhibition of expression of the posttranscriptional regulator MSI1. We also show MSI1 interaction with the 3'-UTR of Gnrhr mRNA. These findings now open the door to future studies of leptin-modulated posttranscriptional pathways.

Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) senses a cell's energy status and environmental levels of nutrients and growth factors. In response, mTORC1 mediates signaling that controls protein translation and cellular metabolism. Although mTORC1 plays a critical role in hematopoiesis, it remains unclear which upstream stimuli regulate mTORC1 activity in the context of hematopoietic stem cells (HSC) maintenance in vivo. In this study, we investigated the function of Rheb, a critical regulator of mTORC1 activity controlled by the PI3K-AKT-TSC axis, both in HSC maintenance in mice at steady-state and in HSC-derived hematopoiesis post-transplantation. In contrast to the severe hematopoietic dysfunction caused by Raptor deletion, which completely inactivates mTORC1, Rheb deficiency in adult mice did not show remarkable hematopoietic failure. Lack of Rheb caused abnormalities in myeloid cells but did not have impact on hematopoietic regeneration in mice subjected to injury by irradiation. As previously reported, Rheb deficiency resulted in defective HSC-derived hematopoiesis post-transplantation. However, while Raptor is essential for HSC competitiveness in vivo, Rheb is dispensable for HSC maintenance under physiological conditions, indicating that the PI3K-AKT-TSC pathway does not contribute to mTORC1 activity for sustaining HSC self-renewal activity at steady-state. Thus, the various regulatory elements that impinge upstream of mTORC1 activation pathways are differentially required for HSC homeostasis in vivo.

MRF Family Genes Are Involved in Translation Control, Especially under Energy-Deficient Conditions, and Their Expression and Functions Are Modulated by the TOR Signaling Pathway.

Dynamic control of protein translation in response to the environment is essential for the survival of plant cells. Target of rapamycin (TOR) coordinates protein synthesis with cellular energy/nutrient availability through transcriptional modulation and phosphorylation of the translation machinery. However, mechanisms of TOR-mediated translation control are poorly understood in plants. Here, we report that Arabidopsis thaliana MRF (MA3 DOMAIN-CONTAINING TRANSLATION REGULATORY FACTOR) family genes encode translation regulatory factors under TOR control, and their functions are particularly important in energy-deficient conditions. Four MRF family genes (MRF1-MRF4) are transcriptionally induced by dark and starvation (DS). Silencing of multiple MRFs increases susceptibility to DS and treatment with a TOR inhibitor, while MRF1 overexpression decreases susceptibility. MRF proteins interact with eIF4A and cofractionate with ribosomes. MRF silencing decreases translation activity, while MRF1 overexpression increases it, accompanied by altered ribosome patterns, particularly in DS. Furthermore, MRF deficiency in DS causes altered distribution of mRNAs in sucrose gradient fractions and accelerates rRNA degradation. MRF1 is phosphorylated in vivo and phosphorylated by S6 kinases in vitro. MRF expression and MRF1 ribosome association and phosphorylation are modulated by cellular energy status and TOR activity. We discuss possible mechanisms of the function of MRF family proteins under normal and energy-deficient conditions and their functional link with the TOR pathway.

Thermotolerant genes essential for survival at a critical high temperature in thermotolerant ethanologenic Zymomonas mobilis TISTR 548

BackgroundHigh-temperature fermentation (HTF) technology is expected to reduce the cost of bioconversion of biomass to fuels or chemicals. For stable HTF, the development of a thermotolerant microbe is indispensable. Elucidation of the molecular mechanism of thermotolerance would enable the thermal stability of microbes to be improved.ResultsThermotolerant genes that are essential for survival at a critical high temperature (CHT) were identified via transposon mutagenesis in ethanologenic, thermotolerant Zymomonas mobilis TISTR 548. Surprisingly, no genes for general heat shock proteins except for degP were included. Cells with transposon insertion in these genes showed a defect in growth at around 39 °C but grew normally at 30 °C. Of those, more than 60% were found to be sensitive to ethanol at 30 °C, indicating that the mechanism of thermotolerance partially overlaps with that of ethanol tolerance in the organism. Products of these genes were classified into nine categories of metabolism, membrane stabilization, transporter, DNA repair, tRNA modification, protein quality control, translation control, cell division, and transcriptional regulation.ConclusionsThe thermotolerant genes of Escherichia coli and Acetobacter tropicalis that had been identified can be functionally classified into 9 categories according to the classification of those of Z. mobilis, and the ratio of thermotolerant genes to total genomic genes in Z. mobilis is nearly the same as that in E. coli, though the ratio in A. tropicalis is relatively low. There are 7 conserved thermotolerant genes that are shared by these three or two microbes. These findings suggest that Z. mobilis possesses molecular mechanisms for its survival at a CHT that are similar to those in E. coli and A. tropicalis. The mechanisms may mainly contribute to membrane stabilization, protection and repair of damage of macromolecules and maintenance of cellular metabolism at a CHT. Notably, the contribution of heat shock proteins to such survival seems to be very low.

Inferring Methionine Sulfoxidation and serine Phosphorylation crosstalk from Phylogenetic analyses

BackgroundThe sulfoxidation of methionine residues within the phosphorylation motif of protein kinase substrates, may provide a mechanism to couple oxidative signals to changes in protein phosphorylation. Herein, we hypothesize that if the residues within a pair of phosphorylatable-sulfoxidable sites are functionally linked, then they might have been coevolving. To test this hypothesis a number of site pairs previously detected on human stress-related proteins has been subjected to analysis using eukaryote ortholog sequences and a phylogenetic approach.ResultsOverall, the results support the conclusion that in the eIF2α protein, serine phosphorylation at position 218 and methionine oxidation at position 222, belong to the same functional network. First, the observed data were much better fitted by Markovian models that assumed coevolution of both sites, with respect to their counterparts assuming independent evolution (p-value = 0.003). Second, this conclusion was robust with respect to the methods used to reconstruct the phylogenetic relationship between the 233 eukaryotic species analyzed. Third, the co-distribution of phosphorylatable and sulfoxidable residues at these positions showed multiple origins throughout the evolution of eukaryotes, which further supports the view of an adaptive value for this co-occurrence. Fourth, the possibility that the coevolution of these two sites might be due to structure-driven compensatory mutations was evaluated. The results suggested that factors other than those merely structural were behind the observed coevolution. Finally, the relationship detected between other modifiable site pairs from ataxin-2 (S814-M815), ataxin-2-like (S211-M215) and Pumilio homolog 1 (S124-M125), reinforce the view of a role for phosphorylation-sulfoxidation crosstalk.ConclusionsFor the four stress-related proteins analyzed herein, their respective pairs of PTM sites (phosphorylatable serine and sulfoxidable methionine) were found to be evolving in a correlated fashion, which suggests a relevant role for methionine sulfoxidation and serine phosphorylation crosstalk in the control of protein translation under stress conditions.

Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2

Appropriate and sequential differentiation of keratinocytes is essential for all functions of the human epidermis. Although transcriptional regulation has proven to be important for keratinocyte differentiation, little is known about the role of translational control. A key mechanism for modulating translation is through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2). A family of different eIF2α kinases function in the integrative stress response to inhibit general protein synthesis coincident with preferential translation of select mRNAs that participate in stress alleviation. Here we demonstrate that translational control through eIF2α phosphorylation is required for normal keratinocyte differentiation. Analyses of polysome profiles revealed that key differentiation genes, including involucrin, are bound to heavy polysomes during differentiation, despite decreased general protein synthesis. Induced eIF2α phosphorylation by the general control nonderepressible 2 (GCN2) protein kinase facilitated translational control and differentiation-specific protein expression during keratinocyte differentiation. Furthermore, loss of GCN2 thwarted translational control, normal epidermal differentiation, and differentiation gene expression in organotypic skin culture. These findings underscore a previously unknown function for GCN2 phosphorylation of eIF2α and translational control in the formation of an intact human epidermis.

Proteogenomics Reveals Enriched Ribosome Assembly and Protein Translation in Pectoralis major of High Feed Efficiency Pedigree Broiler Males.

Background: In production animal agriculture, the cost of feed represents 60–70% of the total cost of raising an animal to market weight. Thus, development of viable biomarkers for feed efficiency (FE, g gain/g feed) to assist in genetic selection of breeding stock remains an important goal in commercial breeding programs.Methods: Global gene (cDNA microarray, RNAseq) and protein expression (shotgun proteomics) analyses have been conducted on breast muscle samples obtained from pedigree broiler males (PedM) exhibiting high and low FE phenotypes. Using the entire datasets (i.e., no cutoffs for significance or fold difference in expression) the number of genes or proteins that were expressed numerically higher or lower in the high FE compared to the low FE phenotype for key terms or functions, e.g., ribosomal, mitochondrial ribosomal, tRNA, RNA binding motif, RNA polymerase, small nuclear ribonucleoprotein, and protein tyrosine phosphatase, were determined. Bionomial distribution analysis (exact) was then conducted on these datasets to determine significance between numerically up or down expression.Results: Processes associated with mitochondrial proteome expression (e.g., mitochondrial ribosomal proteins, mitochondrial transcription, mitochondrial tRNA, and translation) were enriched in breast muscle from the high FE compared to the low FE pedigree male broiler phenotype. Furthermore, the high FE phenotype exhibited enrichment of ribosome assembly (e.g., RNA polymerase, mitochondrial and cytosolic ribosomes, small, and heterogeneous nuclear ribonucleoproteins), as well as nuclear transport and protein translation processes compared to the low FE phenotype. Quality control processes (proteosomes and autophagy) were also enriched in the high FE phenotype. In contrast, the low FE phenotype exhibited enrichment of cytoskeletal proteins, protein tyrosine phosphatases, and tyrosine kinases compared to the high FE phenotype. These results suggest that processes of mitochondrial and cytosolic ribosomal construction, activity, and protein translation would be enhanced in high FE breast muscle, and that phosphorylation of tyrosine moieties of proteins could be prolonged in the high compared to low FE phenotype. The results indicate the presence of a proteogenomic architecture that could enhance ribosome construction, protein translation, and quality control processes and contribute to the phenotypic expression of feed efficiency in this PedM broiler model.

Regulation of Translation by TOR, eIF4E and eIF2α in Plants: Current Knowledge, Challenges and Future Perspectives.

An important step in eukaryotic gene expression is the synthesis of proteins from mRNA, a process classically divided into three stages, initiation, elongation, and termination. Translation is a precisely regulated and conserved process in eukaryotes. The presence of plant-specific translation initiation factors and the lack of well-known translational regulatory pathways in this kingdom nonetheless indicate how a globally conserved process can diversify among organisms. The control of protein translation is a central aspect of plant development and adaptation to environmental stress, but the mechanisms are still poorly understood. Here we discuss current knowledge of the principal mechanisms that regulate translation initiation in plants, with special attention to the singularities of this eukaryotic kingdom. In addition, we highlight the major recent breakthroughs in the field and the main challenges to address in the coming years.

RNA-binding protein SAMD4 regulates skeleton development through translational inhibition of Mig6 expression

Protein translation regulation has essential roles in inflammatory responses, cancer initiation and the pathogenesis of several neurodegenerative disorders. However, the role of the regulation of protein translation in mammalian skeleton development has been rarely elaborated. Here we report that the lack of the RNA-binding protein sterile alpha motif domain containing protein 4 (SAMD4) resulted in multiple developmental defects in mice, including delayed bone development and decreased osteogenesis. Samd4-deficient mesenchymal progenitors exhibit impaired osteoblast differentiation and function. Mechanism study demonstrates that SAMD4 binds the Mig6 mRNA and inhibits MIG6 protein synthesis. Consistent with this, Samd4-deficient cells have increased MIG6 protein level and knockdown of Mig6 rescues the impaired osteogenesis in Samd4-deficient cells. Furthermore, Samd4-deficient mice also display chondrocyte defects, which is consistent with the regulation of MIG6 protein level by SAMD4. These findings define SAMD4 as a previously unreported key regulator of osteoblastogenesis and bone development, implying that regulation of protein translation is an important mechanism governing skeletogenesis and that control of protein translation could have therapeutic potential in metabolic bone diseases, such as osteoporosis.

MiRNAs in cerebrospinal fluid identify patients with MS and specifically those with lipid-specific oligoclonal IgM bands

Background: MicroRNAs (miRNAs) are non-coding RNAs that regulate cellular processes by controlling protein translation and mRNA degradation. Objective: We aimed to explore the miRNA signature of multiple sclerosis (MS) patients versus controls and the possibility that patients with lipid-specific oligolconal IgM bands (LS_OCMB), a predictor of a more severe disease course, may have a distinct profile. Methods: An extensive profile of 754 miRNAs was evaluated in the cerebrospinal fluid (CSF) of 14 women using TaqMan low-density arrays. Differentially expressed miRNAs together with others previously identified in the literature were validated in an extended sample of 86 MS patients (39 LS_OCMB+) and 55 controls. Results: We detected higher levels of miR-150 in MS patients and especially in those with LS_OCMB+. Other miRNAs (miR-328, miR-30a-5p and miR-645) were up-regulated in MS patients compared to controls while miR-21, miR-199a-3p, miR-191, miR-365, miR-106a and miR-146a showed down-regulated expression. Considering only patients with LS_OCMB+, we also detected up-regulation of miR-30a-5p, miR-150 and miR-645 and down-regulation of miR-191 compared to controls. Conclusion: Our study confirms the recent findings regarding the deregulated expression of miR-150 not only with MS but also with the presence of LS_OCMB. This study highlights the potential utility of miRNAs in CSF as biomarkers for MS.

Translational regulation in blood stages of the malaria parasite Plasmodium spp.: systems-wide studies pave the way.

The malaria parasite Plasmodium spp. varies the expression profile of its genes depending on the host it resides in and its developmental stage. Virtually all messenger RNA (mRNA) is expressed in a monocistronic manner, with transcriptional activation regulated at the epigenetic level and by specialized transcription factors. Furthermore, recent systems‐wide studies have identified distinct mechanisms of post‐transcriptional and translational control at various points of the parasite lifecycle. Taken together, it is evident that ‘just‐in‐time’ transcription and translation strategies coexist and coordinate protein expression during Plasmodium development, some of which we review here. In particular, we discuss global and specific mechanisms that control protein translation in blood stages of the human malaria parasite Plasmodium falciparum, once a cytoplasmic mRNA has been generated, and its crosstalk with mRNA decay and storage. We also focus on the widespread translational delay observed during the 48‐hour blood stage lifecycle of P. falciparum—for over 30% of transcribed genes, including virulence factors required to invade erythrocytes—and its regulation by cis‐elements in the mRNA, RNA‐processing enzymes and RNA‐binding proteins; the first‐characterized amongst these are the DNA‐ and RNA‐binding Alba proteins. More generally, we conclude that translational regulation is an emerging research field in malaria parasites and propose that its elucidation will not only shed light on the complex developmental program of this parasite, but may also reveal mechanisms contributing to drug resistance and define new targets for malaria intervention strategies. WIREs RNA 2016, 7:772–792. doi: 10.1002/wrna.1365For further resources related to this article, please visit the WIREs website.