Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection

Ahn, Young Ha; Park, Sunyoung; Choi, Jeong June; Park, Bo Kyung; Rhee, Kyu-Nam; Kang, Eunjoo; Ahn, Soyeon; Lee, Chul‐Ho; Lee, Jong Soo; Inn, Kyung Soo; Cho, Mi La; Park, Sung Hwan; Park, Kyunghee; Park, Hae Jung; Lee, Jae Hyun; Park, Jung Won; Kwon, Nam Hoon; Shim, Hyunbo; Han, Byung Woo; Kim, Pilhan; Lee, Joo Youn; Jeon, Young-Ho; Huh, Jin Won; Jin, Myung; Kim, Sung Hoon

doi:10.1038/nmicrobiol.2016.191

Cited by 71 publications

(111 citation statements)

References 34 publications

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“…Trp supplementation, a condition that promotes the accumulation of Trp metabolites, reduced WARS expression (Figure 3A), while not affecting WARS2 (Figure 3B). Conversely, Trp starvation induced WARS mRNA (Figure 3C) in cell lines with high (A172) and medium (LN18) TDO2 expression, high IDO1 expression (SKOV3) as well as in cells that do not express any Trp-degrading enzymes (LN229) 16,20 . The increase in WARS mRNA upon Trp starvation also translated into increased WARS protein levels as assessed in LN229 glioblastoma cells.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…The MSC protein AIMP1 also has a critical role in innate and adaptive antiviral immunity against influenza A virus infection [21]. In addition, secreted WRS acts as an early warning signal of host infections [22]. Together, these findings suggest that ARSs may act as cellular sensors as well as immunoregulators in the context of infection.…”

Section: Introductionmentioning

confidence: 98%

“…Recent studies identified novel molecular and cellular processes through which ARSs control host immune responses against infections [20][21][22]. EPRS contributes to innate antiviral immunity and promotes viral clearance [20].…”

Section: Introductionmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

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Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeostasis, beyond their intrinsic function as protein synthesis enzymes. Recent discoveries revealed that ubiquitously expressed standby cytoplasmic ARSs sense and respond to danger signals and regulate immunity against infections, indicating their potential as therapeutic targets for infectious diseases. In this review, we discuss ARS-mediated anti-infectious signaling and the emerging role of ARSs in antimicrobial immunity. In contrast to their ability to defend against infection, host ARSs are inevitably co-opted by viruses for survival and propagation. We therefore provide a brief overview of the communication between viruses and the ARS system. Finally, we discuss encouraging new approaches to develop ARSs as therapeutics for infectious diseases.

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“…28 Interestingly, the activity of the FL-TrpRS can be recapitulated by the N-terminal 154 residues, which contain the WHEP domain and the ESE (Fig. 1A).…”

Section: Discussionmentioning

confidence: 98%

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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Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection

Cited by 71 publications

References 34 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

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

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

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