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Angiogenesis induced by aminoacyl-tRNA synthetase deficiency is dependent on AAR but not UPR pathways

ABSTRACT: Angiogenesis induced by aminoacyl-tRNA synthetase deficiency is dependent on AAR but not UPR pathways

PROVIDER: PRJNA534257 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8948490_1.fastq.gz	Fastqsanger.gz
	SRR8948490_2.fastq.gz	Fastqsanger.gz
	SRR8948491_1.fastq.gz	Fastqsanger.gz
	SRR8948491_2.fastq.gz	Fastqsanger.gz
	SRR8948492_1.fastq.gz	Fastqsanger.gz

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Angiogenesis induced by aminoacyl-tRNA synthetase deficiency is dependent on AAR but not UPR pathways

Project description:The amino acid response (AAR) and the unfolded protein response (UPR) pathways are closely interconnected and both implicated in regulation of stress-induced angiogenesis. Two kinases, Gcn2 and Perk, transduce signals from AAR and UPR, respectively, and phosphorylate the common target, eIF2alpha, the key regulator of protein translation. However, this interconnection makes it difficult to specify different contributions of AAR and UPR to angiogenesis. In this study, we generated a zebrafish angiogenic model harboring a loss-of-function mutation in the threonyl-tRNA synthetase (tars) gene. While previous studies approximately implicated both AAR and UPR into the angiogenic phenotypes, our gene expression profiling of the tars-/- and sibling embryos, as well as those with knockdown of either Gcn2 or Perk in both genotypes, reveal that only AAR is activated by the tars-deficiency. Phenotypic validations using genetic and pharmacological interference with AAR and UPR confirm that AAR, but not UPR, is required for the tars-deficiency-induced angiogenesis. Thus, this study demonstrates that the closely interconnected AAR and UPR can be independently activated and differentially regulate angiogenesis, which reflects the specificity and efficiency of multiple stress response pathways that are evolved integrally to benefit the organism by ensuring sensing and responding precisely to different types of stress.

2021-11-03 | GSE130193 | GEO

Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging

Project description:Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging

| PRJNA593256 | ENA

RNA immunoprecipitation and sequencing of aminoacyl-tRNA synthetase-specific genes

Project description:RNA immunoprecipitation and sequencing of aminoacyl-tRNA synthetase-specific genes

| PRJNA492296 | ENA

Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase is associated with Charcot-Marie-Tooth neuropathy

Project description:Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic target for CMT.

2019-10-01 | GSE125311 | GEO

Pseudouridine-mediated translation control of mRNA by methionine aminoacyl tRNA synthetase

Project description:Pseudouridine-mediated translation control of mRNA by methionine aminoacyl tRNA synthetase

| PRJEB41037 | ENA

McFarland2020 - Synthetase sequestration Model:a combined translation and tRNA charging cycle

Project description:The Synthetase Sequestration Model (SSM) is a simplified translation model that considers explicitly two main steps in the process of tRNA aminoacylation: first, the tRNA is bound by the aminoacyl tRNA synthetase, and in a second step, the amino acid is attached to the tRNA. The tRNA then participates in the translation reaction, becoming deacylated as a result. The tRNA exists in states bound, charged and uncharged. In the bound state, the tRNA is bound to the synthetase but uncharged, i.e., the tRNA is sequestered by the synthetase. The model predicts how the balance between the three different tRNA states (empty, bound and charged) changes depending on aminoacyl tRNA synthetase availability.

2020-02-05 | MODEL2001080005 | BioModels

Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging

Project description:Summary Aminoacyl-tRNA synthetases (aaRSs) serve a dual role in charging tRNAs. Their enzymatic activities both provide protein synthesis flux and reduce uncharged tRNA levels. Although uncharged tRNAs can negatively impact bacterial growth, substantial concentrations of tRNAs remain deacylated even under nutrient-rich conditions. Here we show that tRNA charging in Bacillus subtilis is not maximized due to optimization of aaRS production during rapid growth, which prioritizes demands in protein synthesis over charging levels. The presence of uncharged tRNAs is alleviated by precisely tuned translation kinetics and the stringent response, both insensitive to aaRS overproduction but sharply responsive to underproduction, allowing for just-enough aaRS production atop a “fitness cliff”. Notably, we find that the stringent response mitigates fitness defects at all aaRS underproduction levels even without external starvation. Thus, adherence to minimal, flux-satisfying protein production drives limited tRNA charging and provides a basis for the sensitivity and setpoints of an integrated growth-control network.

2020-07-20 | GSE141389 | GEO

Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response"

Project description:Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.

2023-06-09 | GSE155309 | GEO

Two aminoacyl-tRNA synthetase complexes anchored to the Plasmodium surface tRNA import protein

Project description:Aminoacyl-tRNA synthetases (aaRSs) attach amino acids to their cognate transfer RNAs. In eukaryotes, a subset of cytosolic aaRSs is organized into a multi-synthetase complex (MSC), along with specialized scaffolding proteins referred to as aaRS-interacting multifunctional proteins (AIMPs). In Plasmodium, the causative agent of malaria, the tRNA import protein (tRip), is a membrane protein which participates in tRNA trafficking. Here, we show that tRip is also an AIMP. We identified three aaRSs, namely the glutamyl- (ERS), glutaminyl- (QRS), and methionyl- (MRS) tRNA synthetases, which were specifically co-immunoprecipitated with tRip in Plasmodium berghei blood stage parasites. All four proteins contain an N-terminal GST-like domain involved in MSC assembly. Surprisingly, further dissection of GST-like interactions identified two exclusive heterotrimeric complexes: Q-complex (tRip:ERS:QRS) and M-complex (tRip:ERS:MRS). Gel filtration and light scattering suggest a 2:2:2 stoichiometry for both complexes but with distinct biophysical properties and mutational analysis revealed that the GST-like domains of QRS and MRS use different strategies to bind ERS. Furthermore, the modular organization of the assembled aaRSs and the properties of the specific additional modules supported the proposed localization of these complexes at the parasite membrane.

2022-06-09 | PXD033057 | Pride

Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response"

Project description:Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response"

| PRJNA649280 | ENA