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Tryptophanyl-Trna Synthetase As a Potential Therapeutic Target

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Tryptophanyl-Trna Synthetase As a Potential Therapeutic Target International Journal of Molecular Sciences Review Tryptophanyl-tRNA Synthetase as a Potential Therapeutic Target Young Ha Ahn 1,2 , Se-Chan Oh 2,3 , Shengtao Zhou 1,* and Tae-Don Kim 2,3,* 1 Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China; [email protected] 2 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; [email protected] 3 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea * Correspondence: [email protected] (S.Z.); [email protected] (T.-D.K.) Abstract: Tryptophanyl-tRNA synthetase (WRS) is an essential enzyme that catalyzes the ligation of tryptophan (Trp) to its cognate tRNAtrp during translation via aminoacylation. Interestingly, WRS also plays physiopathological roles in diseases including sepsis, cancer, and autoimmune and brain diseases and has potential as a pharmacological target and therapeutic. However, WRS is still generally regarded simply as an enzyme that produces Trp in polypeptides; therefore, studies of the pharmacological effects, therapeutic targets, and mechanisms of action of WRS are still at an emerging stage. This review summarizes the involvement of WRS in human diseases. We hope that this will encourage further investigation into WRS as a potential target for drug development in various pathological states including infection, tumorigenesis, and autoimmune and brain diseases. Keywords: tryptophanyl-tRNA synthetase; sepsis; cancer; Alzheimer’s disease; IFN-γ; kynurenine pathway; tryptophan metabolism Citation: Ahn, Y.H.; Oh, S.-C.; Zhou, S.; Kim, T.-D. Tryptophanyl-tRNA Synthetase as a Potential Therapeutic Target. Int. J. Mol. Sci. 2021, 22, 4523. 1. Introduction https://doi.org/10.3390/ijms22094523 Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate amino acids to cognate tRNAs in protein synthesis. The catalytic activities of ARSs play essential roles in Academic Editor: Amedeo Amedei maintaining cell viability; however, they are also versatile and multifunctional proteins regulated by diverse control mechanisms [1–4]. Several features distinguish eukaryotic Received: 29 March 2021 ARSs from their prokaryotic homologs. The addition of extra domains and sequence Accepted: 23 April 2021 Published: 26 April 2021 adaptations contribute to cellular functions, including cytokine activity associated with inflammation, apoptosis, angiogenesis, and tumorigenesis in mammalian synthetases [5,6]. Publisher’s Note: MDPI stays neutral This review focuses on the roles of eukaryotic tryptophanyl-tRNA synthetase (WRS) in with regard to jurisdictional claims in pathological states and its clinical potential as a pharmacological target. published maps and institutional affil- Elevated levels of WRS are expressed in the bovine pancreas, and its various truncated iations. forms are secreted into bovine pancreatic fluid. Thus, an important role of WRS beyond protein translation has long been suspected [7–9]. Eukaryotic WRS exists as a free cytosolic enzyme that self-aggregates to form large homo-oligomers, rather than associate with a multi-tRNA synthetase complex (MSC). This property of WRS has been identified in higher eukaryotes, but not in prokaryotes [10,11]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Evolutionarily, ARSs have added new domains that have no apparent connection This article is an open access article with aminoacylation. Human WRS has a unique N-terminal extension domain of about distributed under the terms and 150 amino acids that is not present in its prokaryotic counterpart. The extension domain conditions of the Creative Commons is composed of a vertebrate-specific extension of about 50 amino acids, also known as Attribution (CC BY) license (https:// WHEP domain, named after initials of (underlined) WRS, histidyl-tRNA synthetase (HRS), creativecommons.org/licenses/by/ and glutamyl-prolyl-tRNA synthetase (EPRS). WHEP domain includes a specific helix- 4.0/). turn-helix motif and is involved with diverse interactions with other proteins [5,6,12–14] Int. J. Mol. Sci. 2021, 22, 4523. https://doi.org/10.3390/ijms22094523 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4523 2 of 13 (Table1) . Elimination of WHEP domain does not markedly inhibit in vitro aminoacyla- tion activities of several synthetases, indicating that the WHEP domains themselves may provide a non-canonical function unrelated to aminoacylation [15,16]. Among 20 ARSs, EPRS and WRS have similarities, in that they have WHEP domains and are regulated by interferon (IFN)-γ. Human EPRS contains three WHEP domains involved in the formation of the IFN-γ activated inhibitor of translation (GAIT) complex, and controlling the translation of vascular endothelial growth factor A (VEGFA) and ceruloplasmin (Cp) [17,18]. Notably, WRS is the only ARS whose expression is induced by IFN-γ [19–23], the action of which is supposedly mediated by WHEP domain. WRS is also rapidly secreted from immune cells in response to both bacterial and viral infections, suggesting a critical role in inflammatory response. In contrast, other ARSs were not secreted from monocytes upon in vitro microbial infections [24,25]. Full-length WRS (FL-WRS) is alternatively spliced or truncated into mini-WRS (residues 48–471). Proteolytic digestion of WRS by extracellular proteases also produces the N- Int. J. Mol. Sci. 2021terminally, 22, x FOR truncated PEER REVIEW variants T1-WRS (residues 71–471) and T2-WRS (residues 94–471) [20, 3 of 14 Int. J. Mol. Sci. 2021 , 22, x FOR PEER22, 26REVIEW]. The expression of these truncated variants is stimulated by IFN-γ, which plays3 aof 14 central regulatory role in anti-angiogenesis [27–29]. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEWUnderstanding of the biological functions of truncated WRS variants in vascular home-3 of 14 Table 1. Schematic structure of ARSs containing WHEP domain. EPRS and MRS are components of the multi-tRNA syn- Int. J. TableMol. Sci. 1. 2021 Schematic, 22thetase, x FOR structure PEERcomplexostasis REVIEW of ARSs(MSC) [26, 30 containing –and32] the as wellcell WHEP regula as the domain.tory structure activities EPRS and andare propertiescontrolledMRS are components by of specif secretedic phosphorylationof WRSthe multi-tRNA has progressed [5,35–39]. syn-3 of 14WRS, HRS, thetase complexand (MSC) GRS and significantlyexist the in cella free regula [form11,tory20 and,21 activities ,are24, 25induced,33 are]. Numerouscontrolled under various by studies specif pathologicalic havephosphorylation associated conditions [5,35–39]. WRS[12,40–44] with WRS,. The infection, HRS,regulatory activities Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 14 andTable GRS 1. Schematicexist inof aWRS free structure areformcancer, controlled andof ARSs autoimmunity, are inducedbycontaining proteolytic under andWHEP cleavage.various brain domain. diseases.pa Thethological EPRS secreted Consideringand conditions WRSMRS areare cleaved thatcomponents[12,40–44] WRS and. isThe produceof secreted theregulatory multi-tRNA WR duringS activitiesvariants bacte-syn- such mini-, T1- of WRS are controlled byrial proteolytic and viral cleavage. infections, The it secreted has been WRS recently are cleaved identified and produce as a promising WRS variants biomarker such mini-, in patients T1- Int. J. thetaseMol. Sci. complex2021, 22and, x (MSC) FOR T2-WRS. PEER and REVIEW theGST, cell Glutathione regulatory S-transferactivities arease; controlled CD, catalytic by specifdomain;ic phosphorylation ERS, glutamyl-tRNA [5,35–39]. synthetase; WRS, HRS, PRS,3 ofprolyl-tRNA 14 andandTable T2-WRS.GRS 1. Schematic exist GST, synthetase;in a freeGlutathionestructure withform EPRS, andof sepsis ARSsS-transfer glutamyl-prolyl-tRNAare [ induced34containing].ase; This CD,under review WHEP catalytic various summarizesdomain.synthetase; domain; pathological EPRS MRS,ERS, the and conditionsglutam physiopathologicalmethionyl-tRNS MRS areyl-tRNA components[12,40–44] synthetase; synthe. The roles oftase; theregulatory PRS, of HRS,multi-tRNA WRS prolyl-tRNA histidyl-tRNA thatactivities syn- have synthetase; synthetase;ofTablethetase WRS 1. complexare Schematic EPRS,controlledGRS, (MSC) glutamyl-prolyl-tRNA structure glycyl-tRNA by beenand proteolytic the of reported ARSscell synthetase. regula cleavage.containingto synthetase;tory date activitiesThe WHEP and secreted MRS, discusses domain.are methionyl-tRNS controlledWRS EPRS are WRS cleaved byand as specif MRS asynthe potentialandic are phosphorylationproducetase; components HRS, therapeutic WR histidyl-tRNAS variants of [5,35–39]. the target multi-tRNA such synthetase;WRS, for mini-, human HRS, syn- T1- and GRS exist in a free form and are induced under various pathological conditions [12,40–44]. The regulatory activities GRS,andthetase T2-WRS. glycyl-tRNA complex GST, (MSC) synthetase. Glutathione pathologies,and the cellS-transfer regula especiallyase;tory CD, activities infection, catalytic are domain; cancer,controlled autoimmune,ERS, by specifglutamicyl-tRNA phosphorylation Alzheimer’s synthetase; disease [5,35–39]. PRS, (AD). prolyl-tRNA WRS, HRS, synthetase;andofTable WRS GRS 1. are Schematicexist EPRS,controlled in a glutamyl-prolyl-tRNA freestructure by form proteolytic andof ARSs
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