scholarly journals PolyA tracks and poly-lysine repeats are the Achilles heel of Plasmodium falciparum

2018 ◽  
Author(s):  
Slavica Pavlovic Djuranovic ◽  
Jessey Erath ◽  
Ryan J Andrews ◽  
Peter O Bayguinov ◽  
Joyce J Chung ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Synthesis ◽  
Translation Efficiency ◽  
Parasite Protein ◽  
Translational Machinery ◽  
Protein Synthesis Machinery ◽  
Mrna Surveillance ◽  
Endogenous Genes ◽  
Host Life ◽  
Eukaryotic Organisms

AbstractPlasmodium falciparum, the causative agent of human malaria, is an apicomplexan parasite with a complex, multi-host life cycle. Sixty percent of transcripts from its extreme AT-rich (81%) genome possess coding polyadenosine (polyA) runs, distinguishing the parasite from its hosts and other sequenced organisms. Recent studies indicate that transcripts with polyA runs encoding poly-lysine are hot spots for ribosome stalling and frameshifting, eliciting mRNA surveillance pathways and attenuating protein synthesis in the majority of prokaryotic and eukaryotic organisms. Here, we show that the P. falciparum translational machinery is paradigm-breaking. Using bioinformatic and biochemical approaches, we demonstrate that both endogenous genes and reporter sequences containing long polyA runs are efficiently and accurately transcribed and translated in P. falciparum cells. Translation of polyA tracks in the parasite does not elicit any response from mRNA surveillance pathways usually seen in host human cells or organisms with similar AT content. The translation efficiency and accuracy of the parasite protein synthesis machinery reveals a unique role of ribosomes in the evolution and adaptation of P. falciparum to an AU-rich transcriptome and polybasic amino sequences. Finally, we show that the ability of P. falciparum to synthesize long poly-lysine repeats has given this parasite a unique protein exportome and an advantage in infectivity that can be suppressed by addition of exogenous poly-basic polymers.

scholarly journals Plasmodium falciparum translational machinery condones polyadenosine repeats

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Slavica Pavlovic Djuranovic ◽  
Jessey Erath ◽  
Ryan J Andrews ◽  
Peter O Bayguinov ◽  
Joyce J Chung ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Synthesis ◽  
Causative Agent ◽  
Human Cells ◽  
Translational Machinery ◽  
Human Malaria ◽  
Ribosome Stalling ◽  
Mrna Surveillance ◽  
Endogenous Genes ◽  
Stark Contrast

Plasmodium falciparum is a causative agent of human malaria. Sixty percent of mRNAs from its extremely AT-rich (81%) genome harbor long polyadenosine (polyA) runs within their ORFs, distinguishing the parasite from its hosts and other sequenced organisms. Recent studies indicate polyA runs cause ribosome stalling and frameshifting, triggering mRNA surveillance pathways and attenuating protein synthesis. Here, we show that P. falciparum is an exception to this rule. We demonstrate that both endogenous genes and reporter sequences containing long polyA runs are efficiently and accurately translated in P. falciparum cells. We show that polyA runs do not elicit any response from No Go Decay (NGD) or result in the production of frameshifted proteins. This is in stark contrast to what we observe in human cells or T. thermophila, an organism with similar AT-content. Finally, using stalling reporters we show that Plasmodium cells evolved not to have a fully functional NGD pathway.

Regulation of mRNA Translation in Axons

2020 ◽  
Author(s):  
Priyanka Patel ◽  
Pabitra K. Sahoo ◽  
Amar N. Kar ◽  
Jeffery L. Twiss
Keyword(s):  
Protein Synthesis ◽  
Translational Regulation ◽  
Neuronal Cell ◽  
Mrna Translation ◽  
Neuronal Cell Body ◽  
Translational Machinery ◽  
Protein Synthesis Machinery ◽  
Neuronal Systems ◽  
Axonal Protein ◽  
Axonal Protein Synthesis

Axons can extend long distances from the neuronal cell body, and mRNA translation in axons is used to locally generate new proteins in these distal reaches of the neuron’s cytoplasm. Work over the past two decades has shown that axonal mRNA translation occurs in many different organisms and different neuronal systems. The field has progressed substantially over this time, moving from documenting mRNA translation in axons to understanding how axonal mRNA translation is regulated and what the protein products do for the neuron. Translational regulation in axons extends beyond merely controlling activity of the protein synthesis machinery. Transport of mRNAs into axons, stability of the mRNAs within the axons, and sequestration of mRNAs away from the translational machinery each contribute to determining what proteins are generated in axons, as well as when and where those proteins are generated within the axon. It is now known that thousands of different mRNAs can localize into axons. Based on unique responses to different axonal translation regulating stimuli and events, there clearly is specificity for when different mRNA populations are translated. How that specificity is driven is just now beginning to be understood, and studies emerging over the last five years point to multiple mechanisms for imparting specificity for regulation of axonal protein synthesis responses.

scholarly journals Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation

Cell ◽  
2021 ◽  
Vol 184 (9) ◽  
pp. 2520
Author(s):  
Joseph Tcherkezian ◽  
Perry A. Brittis ◽  
Franziska Thomas ◽  
Philippe P. Roux ◽  
John G. Flanagan
Keyword(s):  
Protein Synthesis ◽  
Protein Synthesis Machinery

scholarly journals Functional Role of Tia1/Pub1 and Sup35 Prion Domains: Directing Protein Synthesis Machinery to the Tubulin Cytoskeleton

2014 ◽  
Vol 55 (2) ◽  
pp. 305-318 ◽  
Author(s):  
Xiang Li ◽  
Joseph B. Rayman ◽  
Eric R. Kandel ◽  
Irina L. Derkatch
Keyword(s):  
Protein Synthesis ◽  
Functional Role ◽  
Protein Synthesis Machinery

scholarly journals Microtubules orchestrate local translation to enable cardiac growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Emily A. Scarborough ◽  
Keita Uchida ◽  
Maria Vogel ◽  
Noa Erlitzki ◽  
Meghana Iyer ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Periphery ◽  
Local Translation ◽  
Microtubule Network ◽  
Critical Determinant ◽  
Translation Rate ◽  
Cardiac Growth ◽  
Translational Machinery ◽  
Microtubule Motor ◽  
Discrete Domains

AbstractHypertension, exercise, and pregnancy are common triggers of cardiac remodeling, which occurs primarily through the hypertrophy of individual cardiomyocytes. During hypertrophy, stress-induced signal transduction increases cardiomyocyte transcription and translation, which promotes the addition of new contractile units through poorly understood mechanisms. The cardiomyocyte microtubule network is also implicated in hypertrophy, but via an unknown role. Here, we show that microtubules are indispensable for cardiac growth via spatiotemporal control of the translational machinery. We find that the microtubule motor Kinesin-1 distributes mRNAs and ribosomes along microtubule tracks to discrete domains within the cardiomyocyte. Upon hypertrophic stimulation, microtubules redistribute mRNAs and new protein synthesis to sites of growth at the cell periphery. If the microtubule network is disrupted, mRNAs and ribosomes collapse around the nucleus, which results in mislocalized protein synthesis, the rapid degradation of new proteins, and a failure of growth, despite normally increased translation rates. Together, these data indicate that mRNAs and ribosomes are actively transported to specific sites to facilitate local translation and assembly of contractile units, and suggest that properly localized translation – and not simply translation rate – is a critical determinant of cardiac hypertrophy. In this work, we find that microtubule based-transport is essential to couple augmented transcription and translation to productive cardiomyocyte growth during cardiac stress.

Actomyosin motor in the merozoite of the malaria parasite, Plasmodium falciparum: implications for red cell invasion

1998 ◽  
Vol 111 (13) ◽  
pp. 1831-1839 ◽  
Author(s):  
J.C. Pinder ◽  
R.E. Fowler ◽  
A.R. Dluzewski ◽  
L.H. Bannister ◽  
F.M. Lavin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasma Membrane ◽  
Toxoplasma Gondii ◽  
Malaria Parasite ◽  
Cellular Protein ◽  
Red Cell ◽  
Parasite Protein ◽  
Ionic Detergent ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

The genome of the malaria parasite, Plasmodium falciparum, contains a myosin gene sequence, which bears a close homology to one of the myosin genes found in another apicomplexan parasite, Toxoplasma gondii. A polyclonal antibody was generated against an expressed polypeptide of molecular mass 27,000, based on part of the deduced sequence of this myosin. The antibody reacted with the cognate antigen and with a component of the total parasite protein on immunoblots, but not with vertebrate striated or smooth muscle myosins. It did, however, recognise two components in the cellular protein of Toxoplasma gondii. The antibody was used to investigate stage-specificity of expression of the myosin (here designated Pf-myo1) in P. falciparum. The results showed that the protein is synthesised in mature schizonts and is present in merozoites, but vanishes after the parasite enters the red cell. Pf-myo1 was found to be largely, though not entirely, associated with the particulate parasite cell fraction and is thus presumably mainly membrane bound. It was not solubilised by media that would be expected to dissociate actomyosin or myosin filaments, or by non-ionic detergent. Immunofluorescence revealed that in the merozoite and mature schizont Pf-myo1 is predominantly located around the periphery of the cell. Immuno-gold electron microscopy also showed the presence of the myosin around almost the entire parasite periphery, and especially in the region surrounding the apical prominence. Labelling was concentrated under the plasma membrane but was not seen in the apical prominence itself. This suggests that Pf-myo1 is associated with the plasma membrane or with the outer membrane of the subplasmalemmal cisterna, which forms a lining to the plasma membrane, with a gap at the apical prominence. The results lead to a conjectural model of the invasion mechanism.

Translation initiation factors and active sites of protein synthesis co-localize at the leading edge of migrating fibroblasts

2011 ◽  
Vol 438 (1) ◽  
pp. 217-227 ◽  
Author(s):  
Mark Willett ◽  
Michele Brocard ◽  
Alexandre Davide ◽  
Simon J. Morley
Keyword(s):  
Protein Synthesis ◽  
Cell Migration ◽  
Active Sites ◽  
Membrane Vesicle ◽  
Leading Edge ◽  
Membrane Microdomains ◽  
Plasma Membrane Vesicle ◽  
Translational Machinery ◽  
Initiation Factors ◽  
Scanning Confocal Microscopy

Cell migration is a highly controlled essential cellular process, often dysregulated in tumour cells, dynamically controlled by the architecture of the cell. Studies involving cellular fractionation and microarray profiling have previously identified functionally distinct mRNA populations specific to cellular organelles and architectural compartments. However, the interaction between the translational machinery itself and cellular structures is relatively unexplored. To help understand the role for the compartmentalization and localized protein synthesis in cell migration, we have used scanning confocal microscopy, immunofluorescence and a novel ribopuromycylation method to visualize translating ribosomes. In the present study we show that eIFs (eukaryotic initiation factors) localize to the leading edge of migrating MRC5 fibroblasts in a process dependent on TGN (trans-Golgi network) to plasma membrane vesicle transport. We show that eIF4E and eIF4GI are associated with the Golgi apparatus and membrane microdomains, and that a proportion of these proteins co-localize to sites of active translation at the leading edge of migrating cells.

scholarly journals Mdm38 is a 14-3-3-Like Receptor and Associates with the Protein Synthesis Machinery at the Inner Mitochondrial Membrane

Traffic ◽  
2011 ◽  
Vol 12 (10) ◽  
pp. 1457-1466 ◽  
Author(s):  
Domenico Lupo ◽  
Christine Vollmer ◽  
Markus Deckers ◽  
David U. Mick ◽  
Ivo Tews ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Protein Synthesis Machinery

scholarly journals Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

2013 ◽  
Vol 82 (1) ◽  
pp. 152-164 ◽  
Author(s):  
K. Sony Reddy ◽  
Alok K. Pandey ◽  
Hina Singh ◽  
Tajali Sahar ◽  
Amlabu Emmanuel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Neutralizing Antibodies ◽  
Malaria Vaccine ◽  
Expression System ◽  
Full Length ◽  
Blood Stage ◽  
Parasite Protein ◽  
Content Type ◽  
Erythrocyte Binding ◽  
Blood Stage Malaria

ABSTRACTPlasmodium falciparumreticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number ofP. falciparumstrains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 inEscherichia colithat exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number ofP. falciparumstrains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.P. falciparumhas the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwideP. falciparumstrains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.

Parasitic Infections

2012 ◽  
pp. 190-217
Author(s):  
Jon E. Rosenblatt ◽  
Bobbi S. Pritt
Keyword(s):  
Plasmodium Falciparum ◽  
Toxoplasma Gondii ◽  
Entamoeba Histolytica ◽  
Giardia Lamblia ◽  
Babesia Microti ◽  
Parasitic Infections ◽  
Blastocystis Hominis ◽  
Different Types ◽  
Eukaryotic Organisms ◽  
Parasitic Worms

This chapter covers protozoa, helminths, and arthropods. 1. Protozoa are single-celled, microscopic eukaryotic organisms like amebae and Giardia. Helminths are parasitic worms including nematodes (roundworms), cestodes (tapeworms), and trematodes (flukes). Arthropods, like ticks and mites, are generally considered parasites. Specific organisms reviewed include Giardia lamblia, Cyclospora cayetanensis, Blastocystis hominis, Entamoeba histolytica, Plasmodium falciparum, Babesia microti, and Toxoplasma gondii. Diagnosis and treatment of different types of infection are also reviewed.

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