New functions of aminoacyl-tRNA synthetases beyond translation

Guo, Min; Yang, Xiang‐Lei; Schimmel, Paul

doi:10.1038/nrm2956

Cited by 280 publications

(291 citation statements)

References 67 publications

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“…In addition to its role in aminoacylation, WARS, like many other tRNA synthethases 41-43 , has been implicated in cellular signaling. A truncated version of WARS is secreted in response to IFNγ and elicits angiostatic effects 23 through inhibition of endothelial cell-cell junctions 24 .…”

Section: Discussionmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.

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Section: Discussionmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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Section: Discussionmentioning

confidence: 99%

“…Numerous studies have shown that members of this enzyme family are quite adept at 'moonlighting' in terms of possessing extra capabilities that widen their biological attributes [5][6][7][8] . Studies have indicated that human tyrosyl-, tryptophanyl-and lysyl-tRNA synthetases can be secreted extracellularly and can mimic cytokines [5][6][7][8] . For these extra roles, the human TyrRS and TrpRS require either proteolytic cleavage or alternate splicing to become active [5][6][7][8][9] , whereas LysRS can act like a cytokine without processing 44 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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malaria infection triggers pro-inflammatory responses in humans that are detrimental to host health. Parasite-induced enhancement in cytokine levels correlate with malariaassociated pathologies. Here we show that parasite tyrosyl-tRnA synthetase (PfTyrRs), a housekeeping protein translation enzyme, induces pro-inflammatory responses from host immune cells. PfTyrRs exits from the parasite cytoplasm into the infected red blood cell (iRBC) cytoplasm, from where it is released into the extracellular medium on iRBC lysis. using its ELR peptide motif, PfTyrRs specifically binds to and internalizes into host macrophages, leading to enhanced secretion of the pro-inflammatory cytokines TnF-α and IL-6. PfTyrRs-macrophage interaction also augments expression of adherence-linked host endothelial receptors ICAm-1 and VCAm-1. our description of PfTyrRs as a parasite-secreted protein that triggers proinflammatory host responses, along with its atomic resolution crystal structure in complex with tyrosyl-adenylate, provides a novel platform for targeting PfTyrRs in anti-parasitic strategies.

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“…1 In vertebrates, TrpRS have an N-terminal extension of about 150 amino acids beyond the core catalytic architecture. 2,3 The extension is composed of a vertebrate-specific extension (VSE), also known as WHEP domain (named after the tRNA synthetases (i.e., tryptophanyl (W), histidyl (H), and glutamyl-prolyl (EP) tRNA synthetases) first identified to contain this domain), followed by an eukaryotic specific extension (ESE) 4 (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

“…The WHEP domain has a conserved helix-turn-helix conformation and is dispensable for aminoacylation but critical for regulating the non-enzymatic function of TrpRS in angiogenesis. 2,3 The natural splice variant mini-TrpRS, which lacks most of the WHEP domain but contains the ESE, was found to inhibit VEGF induced angiogenesis. 5,6 Further truncation by leukocyte elastase to remove the first 93 amino acid creates T2-TrpRS that is completely inactive for aminoacylation, but has enhanced anti-angiogenic activity compared to mini-TrpRS.…”

Section: Introductionmentioning

confidence: 99%

An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function

Zhou

et al. 2017

RNA Biology

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Tryptophanyl-tRNA synthetase (TrpRS) in vertebrates contains a N-terminal extension in front of the catalytic core. Proteolytic removal of the N-terminal 93 amino acids gives rise to T2-TrpRS, which has potent anti-angiogenic activity mediated through its extracellular interaction with VE-cadherin. Zinc has been shown to have anti-angiogenic effects and can bind to human TrpRS. However, the connection between zinc and the anti-angiogenic function of TrpRS has not been explored. Here we report that zinc binding can induce structural relaxation in human TrpRS to facilitate the proteolytic generation of a T2-TrpRS-like fragment. The zinc-binding site is likely to be contained within T2-TrpRS, and the zinc-bound conformation of T2-TrpRS is mimicked by mutation H130R. We determined the crystal structure of H130R T2-TrpRS at 2.8 Å resolution, which reveals drastically different conformation from that of wild-type (WT) T2-TrpRS. The conformational change creates larger binding surfaces for VE-cadherin as suggested by molecular dynamic simulations. Surface plasmon resonance analysis indicates more than 50-fold increase in binding affinity of H130R T2-TrpRS for VE-cadherin, compared to WT T2-TrpRS. The enhanced interaction is also confirmed by a cell-based binding analysis. These results suggest that zinc plays an important role in activating TrpRS for angiogenesis regulation.

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New functions of aminoacyl-tRNA synthetases beyond translation

Cited by 280 publications

References 67 publications

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

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

An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function

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