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

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE130193 | GEO | 2021/11/03

REPOSITORIES: GEO

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Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2Î±, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2Î±/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2Î± S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2Î± phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2Î±, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.

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

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