Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses

Bhatt, Tarun Kumar; Khan, Sameena; Dwivedi, Ved Prakash; Banday, Mudassir Meraj; Sharma, Arvind; Chandele, Anmol; Camacho, Noelia; Pouplana, Lluı́s Ribas de; Wu, Yang; Craig, Alister G.; Mikkonen, Antti; Maier, Alexander G.; Yogavel, Manickam; Sharma, Amit

doi:10.1038/ncomms1522

Cited by 59 publications

(70 citation statements)

References 54 publications

(130 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasmodium falciparum possesses 36 aaRSs, which show asymmetric distributions among parasite organelles (7,8,13,14). The presence of appended domains imparts characteristic functions to parasite aaRSs (13)(14)(15). For example, recent studies have revealed cytokine-like functions for malaria tyrosyl-tRNA synthetase (tyrosyl-RS) (15).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Hussain

Yogavel

Sharma

2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS cyt and PfMRS api . Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS cyt ) or proteobacteria/primitive bacteria (PfMRS api ). We show that PfMRS cyt localizes in parasite cytoplasm, while PfMRS api localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with 35 S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. P lasmodium falciparum is the most virulent form of Plasmodium and a causative agent of malaria. The World Health Organization (WHO) estimates that there are ϳ0.62 million deaths due to malaria per year (1). The P. falciparum genome is AT-rich (81%) and codes for ϳ5,300 proteins, with unusual distributions of several residues (2). Almost 60% of encoded proteins appear to be unique to the parasite, reflecting great evolutionary distance between the parasite and the genomes of known eukaryotes (3). The malaria parasite (and the related apicomplexan Toxoplasma gondii) has three translationally active compartments, i.e., cytoplasm, apicoplasts, and mitochondria (4-8). All malaria parasite proteins involved in the protein synthesis machinery are encoded by the nuclear genome. Either these proteins are transported to target organelles or their modified/activated substrates are transported across the organelles to perform required functions (4-9). The primary enzymes responsible for translating genetic code into polypeptide chains are aminoacyl-tRNA synthetases (aaRSs). The canonical function of aaRSs is to ligate a specific amino acid to its cognate tRNA, which is then employed in protein synthesis. The aaRSs are an ancient class of essential enzymes, and their catalytic domains are conserved in all kingdoms (bacteria, archaebacteria, and eukaryotes). On the basis of catalytic domain architecture, aaRSs are classified into two categories, with each class containing ϳ10 aaRSs (10). Although aaRSs perform the basic function of charging tRNA molecules for protein synthesis, a...

show abstract

mentioning

confidence: 99%

“…The presence of appended domains imparts characteristic functions to parasite aaRSs (13)(14)(15). For example, recent studies have revealed cytokine-like functions for malaria tyrosyl-tRNA synthetase (tyrosyl-RS) (15).…”

mentioning

confidence: 99%

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Hussain

Yogavel

Sharma

2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although hemozoin itself does not induce endothelial barrier dysfunction, 47,49 it has been shown to activate NF-kB signaling pathways as shown by increased IL-8 and MCP-1 (CCL2) production in HUVEC. 118 Other parasite derived products such as DNA, 119,120 histones, 121 tRNA synthetase, 120 uric acid 122 and heat shock proteins (HSP) 123 have been shown to activate the host immune system. In the case of histones, they can disrupt endothelia into renal arteries l barrier function.…”

mentioning

confidence: 99%

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

View full text Add to dashboard Cite

Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The hostparasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.

show abstract

“…The few parasite-specific studies available on TyrRS have majorly focused on the structural aspects of the enzyme. A recent comprehensive study highlighted the structural and functional aspect of TyrRS from Plasmodium falciparum (24). The structural analysis of the TyrRS orthologue from L. major reveals several crucial differences between the host and pathogen tyrosyl-tRNA synthetase active sites (13).…”

Section: Discussionmentioning

confidence: 99%

“…immune cells (23)(24)(25). Direct binding of rLdTyrRS to host macrophages was visualized by immunofluorescence analysis.…”

Section: A-c)mentioning

confidence: 99%

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Anand¹,

Madhubala

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes essential for protein synthesis. Apart from their parent aminoacylation activity, several aaRSs perform non-canonical functions in diverse biological processes. The present study explores the twin attributes of Leishmania tyrosyl-tRNA synthetase (LdTyrRS) namely, aminoacylation, and as a mimic of host CXC chemokine. Leishmania donovani is a protozoan parasite. Its genome encodes a single copy of tyrosyl-tRNA synthetase. We first tested the canonical aminoacylation role of LdTyrRS. The recombinant protein was expressed, and its kinetic parameters were determined by aminoacylation assay. To study the physiological role of LdTyrRS in Leishmania, gene deletion mutations were attempted via targeted gene replacement. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. LdTyrRS appears to be an essential gene as the chromosomal null mutants did not survive. Our data also highlights the non-canonical function of L. donovani tyrosyl-tRNA synthetase. We show that LdTyrRS protein is present in the cytoplasm and exits from the parasite cytoplasm into the extracellular medium. The released LdTyrRS functions as a neutrophil chemoattractant. We further show that LdTyrRS specifically binds to host macrophages with its ELR (Glu-Leu-Arg) peptide motif. The ELR-CXCR2 receptor interaction mediates this binding. This interaction triggers enhanced secretion of the proinflammatory cytokines TNF-␣ and IL-6 by host macrophages. Our data indicates a possible immunomodulating role of LdTyrRS in Leishmania infection. This study provides a platform to explore LdTyrRS as a potential target for drug development Aminoacyl-tRNA synthetases (aaRSs) 3 are the central. enzymes in protein translation, providing charged tRNAs for the appropriate construction of peptide chains. The canonical function of aaRSs is to charge specific tRNAs with their cognate amino acids and thereby contribute to accurate mRNA translation during protein synthesis. Thus, aaRSs are essential components of protein synthesis in every living species.Apart from their basic function of charging tRNA molecules for protein synthesis, non-canonical functions like ribosomal RNA biogenesis, angiogenesis, apoptosis, transcriptional regulation, and cell signaling have also been reported for several aaRSs (1, 2). Novel functions of this group of enzymes depend on the addition of one or more new domains or motifs during the course of evolution (3).Tyrosyl-tRNA synthetase (TyrRS) is one such aaRS, which belong to a family of class I synthetases, characterized by a structurally well conserved amino-terminal Rossmann-fold domain, which contains the signature sequences "HIGH" and "KMSKS." The mammalian TyrRS contains a closely homologous endothelial monocyte activating polypeptide II (EMA-PII) domain at the C terminus (4). Under specific conditions, human TyrRS is processed by an elastase enzyme into a free carboxyl-terminal EMAPII-like domain and a second aminoterminal part known as mini-Tyr...

show abstract

Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses

Cited by 59 publications

References 54 publications

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Contact Info

Product

Resources

About