Biopolym. Cell. 2015; 31(4):255-263.
http://dx.doi.org/10.7124/bc.0008E9
Molecular Biomedicine
Autoantibodies against tyrosyl-tRNA synthetase and its separated domains at essential hypertension
1Grom M. Yu., 2Yakovenko L. F., 3Granich V. M., 3Dobrohod A. S., 3Torbas O. O., 3Radchenko A. D., 3Sirenko Yu. M., 2Sidorik L. L., 2Kornelyuk A. I.
  1. Educational and Scientific Center "Institute of Biology"
    Taras Shevchenko National University of Kyiv
    64/13, Volodymyrska Str., Kyiv, Ukraine, 01601
  2. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
  3. National Scientific Center "M. D. Strazhesko Institute of Cardiology, NAMS of Ukraine"
    5, Narodnogo Opolchennya Str., Kyiv, Ukraine, 03680

Abstract

In addition to the key role in biosynthesis some aminoacyl-tRNA synthetases provide non-canonical functions. Particularly, separated fragments of tyrosyl-tRNA synthetase (TyrRS) involved into angiogenesis and inflammation. Meanwhile, the vascular inflammation and endothelial dysfunction are central characteristics of the pathogenesis of essential hypertension (EH). The latest studies highlight a role of antibodies in physiopathology of EH. Aim. We had investigated the full-length TyrRS and its domains as autoantigens in sera of the persons with EH (n = 25), the healthy individuals with family history of the pathology (n = 12), and in the control group of healthy subjects (n = 32). Methods. The recombinant TyrRS and its separated domains coupled with His-tags and generated by Escherichia coli were purified by chromatography on Ni-NTA-agarose. The levels of specific autoantibodies (aAbs) in sera of volunteers were measured by ELISA and confirmed in an immunoblotting assay. Results. Some subjects with elevated levels of aAbs against the full-length enzyme were detected in the cohort studies. 52 % of the persons with EH as immunoreactive against miniTyrRS (p < < 0.001) and 50 % against CTD (p = 0.002) were identified. In 50 % of the healthy individuals with family history of EH (p = 0.037) the levels of anti-CTD aAbs were elevated. Conclusions.The increased levels of aAbs against miniTyrRS and CTD in sera of the persons with EH potentially may be used as a prognostic marker of the disease severity or therapy effectiveness. Moreover, the immunoreactivity of healthy individuals with family history of EH against CTD may be an early marker of hypertension.
Keywords: aminoacyl-tRNA synthetases, miniTyrRS, cytokine, endothelial dysfunction, cardiovascular disease, prognostic marker
Full text: (PDF, in English)

References

[1] Mirande M. Aminoacyl-tRNA synthetase family from prokaryotes and eukaryotes: structural domains and their implications. Prog Nucleic Acid Res Mol Biol. 1991;40:95-142.
[2] Kornelyuk AI. Structural and functional investigation of mammalian tyrosyl-tRNA synthetase. Biopolym Cell. 1998; 14(4):349–59.
[3] Guo M, Yang XL, Schimmel P. New functions of aminoacyl-tRNA synthetases beyond translation. Nat Rev Mol Cell Biol. 2010;11(9):668-74.
[4] Sampath P, Mazumder B, Seshadri V, Gerber CA, Chavatte L, Kinter M, Ting SM, Dignam JD, Kim S, Driscoll DM, Fox PL. Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell. 2004;119(2):195-208.
[5] Greenberg Y, King M, Kiosses WB, Ewalt K, Yang X, Schimmel P, Reader JS, Tzima E. The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. FASEB J. 2008;22(5):1597-605.
[6] Park SG, Schimmel P, Kim S. Aminoacyl tRNA synthetases and their connections to disease. Proc Natl Acad Sci U S A. 2008;105(32):11043-9.
[7] Nangle LA, Zhang W, Xie W, Yang XL, Schimmel P. Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Proc Natl Acad Sci U S A. 2007;104(27):11239-44.
[8] Kunst CB, Mezey E, Brownstein MJ, Patterson D. Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions. Nat Genet. 1997;15(1):91-4.
[9] Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bu­gia­ni M, Schiffmann R, Krägeloh-Mann I, Smeitink JA, Flo­rentz C, Van Coster R, Pronk JC, van der Knaap MS. Mito­chon­drial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet. 2007;39(4):534–9.
[10] Won Lee S, Sun Kang Y, Kim S. Multifunctional proteins in tumorigenesis: aminoacyl-tRNA synthetases and translatio­nal components. Curr Proteomics. 2006;3(4):233–47.
[11] Howard OM, Dong HF, Yang D, Raben N, Nagaraju K, Ro­sen A, Casciola-Rosen L, Härtlein M, Kron M, Yang D, Yiadom K, Dwivedi S, Plotz PH, Oppenheim JJ. Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med. 2002; 196(6):781–91.
[12] Mahler M, Miller FW, Fritzler MJ. Idiopathic inflammatory myopathies and the anti-synthetase syndrome: a comprehensive review. Autoimmun Rev. 2014;13(4-5):367-71.
[13] Jura M, Rychlewski L, Barciszewski J. Comprehensive insight into human aminoacyl-tRNA synthetases as autoantigens in idiopathic inflammatory myopathies. Crit Rev Im­mu­nol. 2007;27(6):559–72.
[14] Kondratiuk IuIu, Sidorik LL, Bobyk VI, Ryabenko DV, Kor­nelyuk AI. Identification of autoantibodies to tyrosil-tRNA synthetase in heart disfunctions. Biopolym Cell. 2010; 26 (5): 373–7.
[15] Korneliuk AI, Kurochkin IV, Matsuka GKh. [Tyrosyl-tRNA synthetase from the bovine liver. Isolation and physico-chemical properties]. Mol Biol (Mosk). 1988;22(1):176-86.
[16] Wakasugi K, Schimmel P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science. 1999;284(5411):147-51.
[17] Wakasugi K, Schimmel P. Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J Biol Chem. 1999;274(33):23155-9.
[18] Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RM. CXC chemokines in angiogenesis. J Leukoc Biol. 2000;68(1):1-8.
[19] Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood. 2008;112(8):3455-64.
[20] Wakasugi K, Slike BM, Hood J, Ewalt KL, Cheresh DA, Schi­mmel P. Induction of angiogenesis by a fragment of human tyrosyl-tRNA synthetase. J Biol Chem. 2002;277(23): 20124–6.
[21] Levanets OV, Naidenov VG, Odynets KA, Woodmaska MI, Matsuka GKh, Kornelyuk AI. Homology of C-terminal non-catalytic domain of mammalian tyrosyl-tRNA synthetase with cylokine EMAP II and non-catalytic domains of methionyl- and phenylalanyl-tRNA synthetases. Biopolym Cell. 1997; 13(6): 474–8.
[22] Kornelyuk AI, Tas MPR, Dubrovsky AL, Murray JC. Cy­okine activity of the non-catalytic EMAP-2-like domain of mammalian tyrosyl-tRNA synthetase. Biopolym Cell. 1999; 15(2):168–72.
[23] Dubrovsky AL, Brown Jn, Kornelyuk AI, Murray JC, Matsu­ka GKh. Bacterial expression of full-length and truncated forms of cytokine EMAP-2 and cytokine-like domain of mammalian tyrosyl-tRNA synthetase. Biopolym Cell. 2000; 16(3): 229–35.
[24] Cheng G, Zhang H, Yang X, Tzima E, Ewalt KL, Schimmel P, Faber JE. Effect of mini-tyrosyl-tRNA synthetase on ischemic angiogenesis, leukocyte recruitment, and vascular permeability. Am J Physiol Regul Integr Comp Physiol. 2008;295(4):R1138-46.
[25] Zeng R, Chen YC, Zeng Z, Liu WQ, Jiang XF, Liu R, Qiang O, Li X. Effect of mini-tyrosyl-tRNA synthetase/mini-tryptophanyl-tRNA synthetase on ischemic angiogenesis in rats: proliferation and migration of endothelial cells. Heart Vessels. 2011;26(1):69-80.
[26] Zeng R, Chen YC, Zeng Z, Liu XX, Liu R, Qiang O, Li X. Inhibition of mini-TyrRS-induced angiogenesis response in endothelial cells by VE-cadherin-dependent mini-TrpRS. Heart Vessels. 2012;27(2):193-201.
[27] Ivakhno SS, Kornelyuk AI. Cytokine-like activities of some aminoacyl-tRNA synthetases and auxiliary p43 cofactor of aminoacylation reaction and their role in oncogenesis. Exp Oncol. 2004;26(4):250-5. PMID: 15627054
[28] Ling Z, Yanling Z, Zhe F, Kui C, Xiushi Z, Min Y, Wei M. Recombinant human tyrosyl-tRNA synthetase, a novel thrombopoietic agent. Eur J Pharmacol. 2014;738:293-300.
[29] McCormick ME, Rojas M, Moser-Katz T, Tzima E, Reader JS. Natural aminoacyl tRNA synthetase fragment enhances cardiac function after myocardial infarction. PLoS One. 2014;9(10):e109325.
[30] Zeng R, Chen YC, Zeng Z, Liu WQ, Liu XX, Liu R, Qiang O, Li X. Different angiogenesis effect of mini-TyrRS/mini-TrpRS by systemic administration of modified siRNAs in rats with acute myocardial infarction. Heart Vessels. 2010;25(4):324-32.
[31] Chan CT, Lieu M, Toh BH, Kyaw TS, Bobik A, Sobey CG, Drummond GR. Antibodies in the pathogenesis of hypertension. Biomed Res Int. 2014;2014:504045.
[32] Kondratiuk YuYu, Babaryk MA, and Kornelyuk OI. Bac­te­rial expression optimization of mammalian tyrosyl-tRNA syn­thetase on strain Escherichia coli BL21 (DE3) pLysE cultivation. Mikrobiol Biotekhnol. 2009; 4(8):6–12.
[33] Suryaprabha P, Padma T, Rao UB. Increased serum IgG levels in essential hypertension. Immunol Lett. 1984;8(3):143-5.
[34] Ebringer A, Doyle AE. Raised serum IgG levels in hypertension. Br Med J. 1970;2(5702):146-8.
[35] Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002;69(4):258-71.
[36] Gross WL, Trabandt A, Reinhold-Keller E. Diagnosis and evaluation of vasculitis. Rheumatology (Oxford). 2000;39(3):245-52.
[37] Silva-Filho JL, Souza MC, Henriques Md, Morrot A, Savino W, Nunes MP, Caruso-Neves C, Pinheiro AA. AT1 receptor-mediated angiotensin II activation and chemotaxis of T lymphocytes. Mol Immunol. 2011;48(15-16):1835-43.
[38] Zhou CC, Irani RA, Dai Y, Blackwell SC, Hicks MJ, Ra­min SM, Kellems RE, Xia Y. Autoantibody-mediated IL-6-dependent endothelin-1 elevation underlies pathogenesis in a mouse model of preeclampsia. J Immunol. 2011;186(10): 6024–34.
[39] Piascik MT, Perez DM. Alpha1-adrenergic receptors: new insights and directions. J Pharmacol Exp Ther. 2001;298(2):403-10.
[40] Jahns R, Boivin V, Hein L, Triebel S, Angermann CE, Ertl G, Lohse MJ. Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest. 2004;113(10):1419-29.
[41] Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3(8):a003947.
[42] Liao DF, Jin ZG, Baas AS, Daum G, Gygi SP, Aebersold R, Berk BC. Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J Biol Chem. 2000;275(1):189-96.
[43] Pockley AG, De Faire U, Kiessling R, Lemne C, Thulin T, Frostegård J. Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hy­pertens. 2002;20(9):1815–20.
[44] Pockley AG, Wu R, Lemne C, Kiessling R, de Faire U, Frostegård J. Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension. 2000;36(2):303-7.
[45] Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep. 2010;12(6):448-55.
[46] Yang X-L, Liu J, Skene RJ, McRee DE, Schimmel P. Crystal structure of an EMAP-II-like cytokine released from a human tRNA synthetase. Helv Chim Acta. 2003;86(4):1246–57
[47] Ermanoska B, Motley WW, Leitão-Gonçalves R, Assel­bergh B, Lee LH, De Rijk P, Sleegers K, Ooms T, Godenschwege TA, Timmerman V, Fischbeck KH, Jordanova A. CMT-as­sociated mutations in glycyl- and tyrosyl-tRNA synthe­tases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila. Neurobiol Dis. 2014;68:180–9.