What do aminoacyl synthetases do?

Aminoacyl-tRNA synthetases ensure that the proper amino acids are used to build proteins

When a ribosome pairs a "CGC" tRNA with "GCG" codon, it expects to find an alanine carried by the tRNA. It has no way of checking; each tRNA is matched with its amino acid long before it reaches the ribosome. The match is made by a collection of remarkable enzymes, the aminoacyl-tRNA synthetases. These enzymes charge each tRNA with the proper amino acid, thus allowing each tRNA to make the proper translation from the genetic code of DNA into the amino acid code of proteins. For more information on tRNA, see the previous Molecule of the Month.

Most cells make twenty different aminoacyl-tRNA synthetases, one for each type of amino acid. These twenty enzymes are widely different, each optimized for function with its own particular amino acid and the set of tRNA molecules appropriate to that amino acid. The one shown here, which charges aspartic acid onto the proper tRNA (entry 1asz ), is a dimer of two identical subunits (colored blue and green, the two tRNA molecules are colored red). Others are small monomers or large monomers, or dimers, or even tetramers of one or more different types of subunits. Some have wildly exotic shapes, such as the serine enzyme (entry 1set ). The structures of nearly all of these different enzymes are available in the PDB.

As you might expect, many of these enzymes recognize their tRNA molecules using the anticodon. But this may not be possible in some cases. Take serine, for instance. Six different codons specify serine, so seryl-tRNA synthetase must recognize six tRNA molecules with six different anticodons, including AGA and GCU, which are entirely different from one another. So, tRNA molecules are also recognized using segments on the acceptor end and bases elsewhere in the molecule. One base in particular, number 73 in the sequence, seems to play a pivotal role in many cases, and has been termed the discriminator base. In other cases, however, it is completely ignored. Note also that each enzyme must recognize its own tRNA molecules, but at the same time, it must not bind to any of the other ones. So, each tRNA has a set of positive interactions that match up the proper tRNA with the proper enzyme, and a set of negative interactions that block binding of improper pairs. For instance, the aspartyl-tRNA synthetase shown here (entry 1asz ) recognizes the discriminator base and 4 bases around the anticodon. But, one other base, guanine 37, is not used in binding, but must be methylated to ensure that the tRNA does not bind improperly to the arginyl-tRNA synthetase.

Recent analyses of entire genomes revealed a big surprise: some organisms don't have genes for all twenty aminoacyl-tRNA synthetases. They do, however, use all twenty amino acids to construct their proteins. The solution to this paradox revealed, as is often the case in living cells, that more complex mechanisms are used. For instance, some bacteria do not have an enzyme for charging glutamine onto its tRNA. Instead, a single enzyme adds glutamic acid to all of the glutamic acid tRNA molecules and to all of the glutamine tRNA molecules. A second enzyme then converts the glutamic acid into glutamine on the latter tRNA molecules, forming the proper pair.

In this picture, five complexes of an aminoacyl-tRNA synthetase with tRNA are shown, aligned so that the tRNA molecules (shown in red) are in the same orientation. Notice that the enzymes approach the tRNA from different angles. The isoleucine (entry 1ffy ), valine (entry 1gax ) and glutamine (entry 1euq ) enzymes cradle the tRNA, gripping the anticodon loop (at the bottom in each tRNA), and placing the amino-acid acceptor end of the tRNA in the active site (at the top right in each tRNA). These all share a similar protein framework, known as "Type I," approaching the tRNA similarly and adding the amino acid to the last 2' hydroxyl group in the tRNA. The phenlyalanine (entry 1eiy ) and threonine (entry 1qf6 ) enzymes are part of a second class of enzymes, known as "Type II." They approach the tRNA from the other side, and add the amino acid to the other free hydroxyl on the last tRNA base.

Aminoacyl-tRNA synthetases must perform their tasks with high accuracy. Every mistake they make will result in a misplaced amino acid when new proteins are constructed. These enzymes make about one mistake in 10,000. For most amino acids, this level of accuracy is not too difficult to achieve. Most of the amino acids are quite different from one another, and, as mentioned before, many parts of the different tRNA are used for accurate recognition. But in a few cases, it is difficult to choose just the right amino acids and these enzymes must resort to special techniques.

Isoleucine is a particularly difficult example. It is recognized by an isoleucine-shaped hole in the enzyme, which is too small to fit larger amino acids like methionine and phenylalanine, and too hydrophobic to bind anything with polar sidechains. But, the slightly smaller amino acid valine, different by only a single methyl group, also fits nicely into this pocket, binding instead of isoleucine in about 1 in 150 times. This is far too many errors, so corrective steps must be taken. Isoleucyl-tRNA synthetase (PDB entry 1ffy ) solves this problem with a second active site, which performs an editing reaction. Isoleucine does not fit into this site, but errant valine does. The mistake is then cleaved away, leaving the tRNA ready for a properly-placed isoleucine amino acid. This proofreading step improves the overall error rate to about 1 in 3,000.

These enzymes are not gentle with tRNA molecules. The structure of glutaminyl-tRNA synthetase with its tRNA (entry 1gtr ) is a good example. The enzyme firmly grips the anticodon, spreading the three bases widely apart for better recognition. At the other end, the enzyme unpairs one base at the beginning of the chain, seen curving upward here, and kinks the long acceptor end of the chain into a tight hairpin, seen here curving downward. This places the 2' hydroxyl on the last nucleotide in the active site, where ATP and the amino acid (not present in this structure) are bound.

This illustration was created with RasMol, using a backbone representation for the protein (chain A) and spacefilling representations for the tRNA chain (chain B) and the ATP molecule (residue name ATP). You can create similar pictures by clicking on the accession code above, and then picking one of the options for 3D viewing. Try looking also at the many protein sidechains that interact with the tRNA.

April 2001, David Goodsell

• 
  Access through your institution

Volume 111, May 2018, Pages 400-414

https://doi.org/10.1016/j.ijbiomac.2017.12.157Get rights and content

Aminoacyl-tRNA synthetase

View full text

mTOR Contributes to the Proteome Diversity through Transcriptome-Wide Alternative Splicing.

Cheng S, Fahmi NA, Park M, Sun J, Thao K, Yeh HS, Zhang W, Yong J. Cheng S, et al. Int J Mol Sci. 2022 Oct 17;23(20):12416. doi: 10.3390/ijms232012416. Int J Mol Sci. 2022. PMID: 36293270 Free PMC article.

1. Pang, Y. L., Poruri, K. & Martinis, S. A. tRNA synthetase: tRNA aminoacylation and beyond. Wiley Interdiscip. Rev. RNA 5, 461–480 (2014).

   Article  CAS  PubMed  PubMed Central  Google Scholar 

2. Wellner, K., Betat, H. & Morl, M. A tRNA’s fate is decided at its 3’ end: collaborative actions of CCA-adding enzyme and RNases involved in tRNA processing and degradation. Biochim. Biophys. Acta Gene Regul. Mech. 1861, 433–441 (2018).

   Article  CAS  PubMed  Google Scholar 

3. Kwon, N. H., Fox, P. L. & Kim, S. Aminoacyl-tRNA synthetases as therapeutic targets. Nat. Rev. Drug Discov. 18, 629–650 (2019).

4. Antonellis, A. & Green, E. D. The role of aminoacyl-tRNA synthetases in genetic diseases. Annu. Rev. Genomics Hum. Genet. 9, 87–107 (2008).

   Article  CAS  PubMed  Google Scholar 

5. Rajendran, V., Kalita, P., Shukla, H., Kumar, A. & Tripathi, T. Aminoacyl-tRNA synthetases: structure, function, and drug discovery. Int. J. Biol. Macromol. 111, 400–414 (2018).

   Article  CAS  PubMed  Google Scholar 

6. Wang, M. & Sips, P. Wars2 is a determinant of angiogenesis. Nat. Commun. 7, 12061 (2016).

7. Jafarnejad, S. M., Kim, S. H. & Sonenberg, N. Aminoacylation of proteins: new targets for the old arsenal. Cell Metab. 27, 1–3 (2018).

   Article  CAS  PubMed  Google Scholar 

8. Jeong, S. J., Park, S., Nguyen, L. T. & Hwang, J. A threonyl-tRNA synthetase-mediated translation initiation machinery. Nat. Commun. 10, 1357 (2019).

9. Ho, D. H. et al. LRRK2 impairs autophagy by mediating phosphorylation of leucyl-tRNA synthetase. Cell. Biochem. Funct. 36, 431–442 (2018).

   Article  CAS  PubMed  Google Scholar 

10. Fu, C. Y., Wang, P. C. & Tsai, H. J. Competitive binding between Seryl-tRNA synthetase/YY1 complex and NFKB1 at the distal segment results in differential regulation of human vegfa promoter activity during angiogenesis. Nucleic Acids Res. 45, 2423–2437 (2017).

    Article  CAS  PubMed  Google Scholar 

11. Jin, M. Unique roles of tryptophanyl-tRNA synthetase in immune control and its therapeutic implications. Exp. Mol. Med. 51, 1 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

12. Lee, E. Y., Kim, S. & Kim, M. H. Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases. Biochem. Pharmacol. 154, 424–434 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

13. Liang, D., Halpert, M. M., Konduri, V. & Decker, W. K. Stepping out of the cytosol: AIMp1/p43 potentiates the link between innate and adaptive immunity. Int. Rev. Immunol. 34, 367–381 (2015).

    Article  CAS  PubMed  Google Scholar 

14. Itoh, M. et al. Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy. Brain 142, 560–573 (2019).

    Article  PubMed  Google Scholar 

15. Selva-O’Callaghan, A. et al. Classification and management of adult inflammatory myopathies. Lancet Neurol. 17, 816–828 (2018).

    Article  PubMed  Google Scholar 

16. Betteridge, Z., Gunawardena, H., North, J., Slinn, J. & McHugh, N. Anti-synthetase syndrome: a new autoantibody to phenylalanyl transfer RNA synthetase (anti-Zo) associated with polymyositis and interstitial pneumonia. Rheumatology (Oxford) 46, 1005–1008 (2007).

    Article  CAS  Google Scholar 

17. Damoiseaux, J. et al. Autoantibodies in idiopathic inflammatory myopathies: clinical associations and laboratory evaluation by mono- and multispecific immunoassays. Autoimmun. Rev. 18, 293–305 (2019).

    Article  CAS  PubMed  Google Scholar 

18. Lee, H. C., Lee, E. S. & Uddin, M. B. Released tryptophanyl-tRNA synthetase stimulates innate immune responses against viral infection. J. Virol. https://doi.org/10.1128/jvi.01291-18 (2019).

19. Anand, S. & Madhubala, R. Twin attributes of tyrosyl-tRNA synthetase of Leishmania donovani: a housekeeping protein translation enzyme and a mimic of host chemokine. J. Biol. Chem. 291, 17754–17771 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

20. Bhatt, T. K. et al. Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses. Nat. Commun. 2, 530 (2011).

    Article  PubMed  CAS  Google Scholar 

21. Ramirez, B. L. et al. Brugia malayi asparaginyl-transfer RNA synthetase induces chemotaxis of human leukocytes and activates G-protein-coupled receptors CXCR1 and CXCR2. J. Infect. Dis. 193, 1164–1171 (2006).

    Article  CAS  PubMed  Google Scholar 

22. Kron, M. A., Metwali, A., Vodanovic-Jankovic, S. & Elliott, D. Nematode asparaginyl-tRNA synthetase resolves intestinal inflammation in mice with T-cell transfer colitis. Clin. Vaccine Immunol. 20, 276–281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

23. Hameed, A. et al. Immune response to Brugia malayi asparaginyl-tRNA synthetase in Balb/c mice and human clinical samples of lymphatic filariasis. Lymphatic Res. Biol. 17, 447–456 (2019).

    Article  CAS  Google Scholar 

24. Kron, M. A., Wang, C., Vodanovic-Jankovic, S., Howard, O. M. & Kuhn, L. A. Interleukin-8-like activity in a filarial asparaginyl-tRNA synthetase. Mol. Biochem. Parasitol. 185, 66–69 (2012).

    Article  CAS  PubMed  Google Scholar 

25. Baddal, B. et al. Dual RNA-seq of nontypeable Haemophilus influenzae and host cell transcriptomes reveals novel insights into host-pathogen cross talk. mBio 6, e01765–01715 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

26. Montoya-Rosales, A. et al. lysX gene is differentially expressed among Mycobacterium tuberculosis strains with different levels of virulence. Tuberculosis (Edinb.) 106, 106–117 (2017).

    Article  CAS  Google Scholar 

27. Kirubakar, G. et al. Proteome analysis of a M. avium mutant exposes a novel role of the bifunctional protein LysX in the regulation of metabolic activity. J. Infect. Dis. 218, 291–299 (2018).

    Article  CAS  PubMed  Google Scholar 

28. Maloney, E. et al. The two-domain LysX protein of Mycobacterium tuberculosis is required for production of lysinylated phosphatidylglycerol and resistance to cationic antimicrobial peptides. PLoS Pathog. 5, e1000534 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

29. Manickam, Y. et al. Drug targeting of one or more aminoacyl-tRNA synthetase in the malaria parasite Plasmodium falciparum. Drug Discov. Today 23, 1233–1240 (2018).

    Article  CAS  PubMed  Google Scholar 

30. Grube, C. D. & Roy, H. A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery. RNA Biol. 15, 659–666 (2018).

    Article  PubMed  Google Scholar 

31. Seiradake, E. et al. Crystal structures of the human and fungal cytosolic Leucyl-tRNA synthetase editing domains: a structural basis for the rational design of antifungal benzoxaboroles. J. Mol. Biol. 390, 196–207 (2009).

    Article  CAS  PubMed  Google Scholar 

32. Barros-Alvarez, X. et al. The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate. Acta Crystallograph. F Struct. Biol. Commun. 74, 245–254 (2018).

    Article  CAS  Google Scholar 

33. Nakama, T., Nureki, O. & Yokoyama, S. Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-tRNA synthetase. J. Biol. Chem. 276, 47387–47393 (2001).

    Article  CAS  PubMed  Google Scholar 

34. Jain, V. et al. Targeting prolyl-tRNA synthetase to accelerate drug discovery against malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, and coccidiosis. Structure 25, 1495–1505.e1496 (2017).

    Article  CAS  PubMed  Google Scholar 

35. Hewitt, S. N. et al. Biochemical and structural characterization of selective allosteric inhibitors of the Plasmodium falciparum drug target, prolyl-tRNA-synthetase. ACS Infect. Dis. 3, 34–44 (2017).

    Article  CAS  PubMed  Google Scholar 

36. Palencia, A. et al. Cryptosporidium and toxoplasma parasites are inhibited by a benzoxaborole targeting leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 60, 5817–5827 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

37. Huang, W. et al. Structure-guided design of novel Trypanosoma brucei methionyl-tRNA synthetase inhibitors. Eur. J. Med. Chem. 124, 1081–1092 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

38. Gudzera, O. I. et al. Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase. Bioorg. Med. Chem. 24, 1023–1031 (2016).

    Article  CAS  PubMed  Google Scholar 

39. Fang, P. et al. Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase. Nat. Commun. 6, 6402 (2015).

    Article  CAS  PubMed  Google Scholar 

40. Herman, J. D. et al. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci. Transl. Med. 7, 288ra277 (2015).

    Article  CAS  Google Scholar 

41. Zhang, Z. et al. 5-Fluoroimidazo[4,5-b]pyridine is a privileged fragment that conveys bioavailability to potent trypanosomal methionyl-tRNA synthetase inhibitors. ACS Infect. Dis. 2, 399–404 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

42. Baragana, B. et al. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc. Natl Acad. Sci. USA 116, 7015–7020 (2019).

43. Fang, P. et al. Structural basis for specific inhibition of tRNA synthetase by an ATP competitive inhibitor. Chem. Biol. 22, 734–744 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

44. Kato, N. et al. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538, 344–349 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

45. Ojo, K. K. et al. Brucella melitensis methionyl-tRNA-synthetase (MetRS), a potential drug target for Brucellosis. PLoS ONE 11, e0160350 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

46. Palencia, A. et al. Discovery of novel oral protein synthesis inhibitors of Mycobacterium tuberculosis that target leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 60, 6271–6280 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

47. Skupinska, M. et al. Natural compounds as inhibitors of tyrosyl-tRNA synthetase. Microb. Drug Resist. 23, 308–320 (2017).

    Article  CAS  PubMed  Google Scholar 

48. Rock, F. L. et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316, 1759–1761 (2007).

    Article  CAS  PubMed  Google Scholar 

49. Li, X. et al. Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy) benzo[c.] [1, 2] oxaborol-1(3H)-ol. (GSK656) J. Med. Chem. 60, 8011–8026 (2017).

    Article  CAS  PubMed  Google Scholar 

50. Stana, A. et al. Antioxidant activity and antibacterial evaluation of new thiazolin-4-one derivatives as potential tryptophanyl-tRNA synthetase inhibitors. J. Enzyme Inhib. Med. Chem. 34, 898–908 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

51. Nayak, S. U. et al. Safety, tolerability, systemic exposure, and metabolism of CRS3123, a methionyl-tRNA synthetase inhibitor developed for treatment of Clostridium difficile, in a Phase 1 study. Antimicrob. Agents Chemother. https://doi.org/10.1128/aac.02760-16 (2017).

52. Matsunaga, T. et al. Analysis of gene expression during maturation of immature dendritic cells derived from peripheral blood monocytes. Scand. J. Immunol. 56, 593–601 (2002).

    Article  CAS  PubMed  Google Scholar 

53. Krause, S. W. et al. Differential screening identifies genetic markers of monocyte to macrophage maturation. J. Leukoc. Biol. 60, 540–545 (1996).

    Article  CAS  PubMed  Google Scholar 

54. Lee, Y. N., Nechushtan, H., Figov, N. & Razin, E. The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcepsilonRI-activated mast cells. Immunity 20, 145–151 (2004).

    Article  CAS  PubMed  Google Scholar 

55. Yannay-Cohen, N. et al. LysRS serves as a key signaling molecule in the immune response by regulating gene expression. Mol. Cell 34, 603–611 (2009).

    Article  CAS  PubMed  Google Scholar 

56. Ofir-Birin, Y. et al. Structural switch of lysyl-tRNA synthetase between translation and transcription. Mol. Cell 49, 30–42 (2013).

    Article  CAS  PubMed  Google Scholar 

57. Casas-Tinto, S., Lolo, F. N. & Moreno, E. Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA synthetase by loser cells recruits haemocytes during cell competition. Nat. Commun. 6, 10022 (2015).

    Article  CAS  PubMed  Google Scholar 

58. Noh, K. T. et al. Resveratrol regulates naive CD 8+ T-cell proliferation by upregulating IFN-gamma-induced tryptophanyl-tRNA synthetase expression. BMB Rep. 48, 283–288 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

59. Park, S. G. et al. Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response. Proc. Natl Acad. Sci. USA 102, 6356–6361 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

60. Jobin, P. G. & Solis, N. Matrix metalloproteinases inactivate the proinflammatory functions of secreted moonlighting tryptophanyl-tRNA synthetase. J. Biol. Chem. 294, 12866–12879 (2019).

61. Mahler, M., Miller, F. W. & Fritzler, M. J. Idiopathic inflammatory myopathies and the anti-synthetase syndrome: a comprehensive review. Autoimmun. Rev. 13, 367–371 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

62. Gallay, L., Gayed, C. & Hervier, B. Antisynthetase syndrome pathogenesis: knowledge and uncertainties. Curr. Opin. Rheumatol. 30, 664–673 (2018).

    Article  CAS  PubMed  Google Scholar 

63. Ascherman, D. P. Role of Jo-1 in the immunopathogenesis of the anti-synthetase syndrome. Curr. Rheumatol. Rep. 17, 56 (2015).

    Article  PubMed  CAS  Google Scholar 

64. Stone, K. B. et al. Anti-Jo-1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy. Arthritis Rheum. 56, 3125–3131 (2007).

    Article  CAS  PubMed  Google Scholar 

65. Lega, J. C. et al. The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome. Autoimmun. Rev. 13, 883–891 (2014).

    Article  CAS  PubMed  Google Scholar 

66. Kaneko, Y., Hanaoka, H., Hirakata, M., Takeuchi, T. & Kuwana, M. Distinct arthropathies of the hands in patients with anti-aminoacyl tRNA synthetase antibodies: usefulness of autoantibody profiles in classifying patients. Rheumatology (Oxford) 53, 1120–1124 (2014).

    Article  CAS  Google Scholar 

67. Marie, I. et al. Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome. Autoimmun. Rev. 11, 739–745 (2012).

    Article  CAS  PubMed  Google Scholar 

68. Pinal-Fernandez, I. et al. A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies. Rheumatology (Oxford) 56, 999–1007 (2017).

    Article  CAS  Google Scholar 

69. Hamaguchi, Y. et al. Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS ONE 8, e60442 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

70. Shi, J. et al. Clinical profiles and prognosis of patients with distinct antisynthetase autoantibodies. J. Rheumatol. 44, 1051–1057 (2017).

    Article  CAS  PubMed  Google Scholar 

71. Aggarwal, R. et al. Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients. Ann. Rheum. Dis. 73, 227–232 (2014).

    Article  PubMed  Google Scholar 

72. Howard, O. M. et al. Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J. Exp. Med. 196, 781–791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

73. Park, J. S. et al. Unique N-terminal extension domain of human asparaginyl-tRNA synthetase elicits CCR3-mediated chemokine activity. Int. J. Biol. Macromol. 120, 835–845 (2018).

    Article  CAS  PubMed  Google Scholar 

74. Fernandez, I. et al. Functional redundancy of MyD88-dependent signaling pathways in a murine model of histidyl-transfer RNA synthetase-induced myositis. J. Immunol. 191, 1865–1872 (2013).

    Article  CAS  PubMed  Google Scholar 

75. Hervier, B. & Perez, M. Involvement of NK cells and NKp30 pathway in antisynthetase syndrome. J. Immunol. 197, 1621–1630 (2016).

76. Ascherman, D. P., Oriss, T. B., Oddis, C. V. & Wright, T. M. Critical requirement for professional APCs in eliciting T cell responses to novel fragments of histidyl-tRNA synthetase (Jo-1) in Jo-1 antibody-positive polymyositis. J. Immunol. 169, 7127–7134 (2002).

    Article  CAS  PubMed  Google Scholar 

77. Katsumata, Y. et al. Species-specific immune responses generated by histidyl-tRNA synthetase immunization are associated with muscle and lung inflammation. J. Autoimmun. 29, 174–186 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

78. Galindo-Feria, A. S. et al. Pro-inflammatory histidyl-tRNA synthetase-specific CD4(+) T cells in the blood and lung of patients with idiopathic inflammatory myopathies. Arthritis Rheumatol., https://doi.org/10.1002/art.41075 (2019).

79. Dzangue-Tchoupou, G., Allenbach, Y., Preusse, C., Stenzel, W. & Benveniste, O. Mass cytometry reveals an impairment of B cell homeostasis in anti-synthetase syndrome. J. Neuroimmunol. 332, 212–215 (2019).

    Article  CAS  PubMed  Google Scholar 

80. Fernandes-Cerqueira, C. et al. Patients with anti-Jo1 antibodies display a characteristic IgG Fc-glycan profile which is further enhanced in anti-Jo1 autoantibodies. Sci. Rep. 8, 17958 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

81. Koch, M. W. et al. Global transcriptome profiling of mild relapsing-remitting versus primary progressive multiple sclerosis. Eur. J. Neurol. 25, 651–658 (2018).

    Article  CAS  PubMed  Google Scholar 

82. Chen, J. et al. Increased TTS expression in patients with rheumatoid arthritis. Clin. Exp. Med. 15, 25–30 (2015).

    Article  PubMed  CAS  Google Scholar 

83. Wang, C. Y. et al. Decreased IDO activity and increased TTS expression break immune tolerance in patients with immune thrombocytopenia. J. Clin. Immunol. 31, 643–649 (2011).

    Article  CAS  PubMed  Google Scholar 

84. Zhang, Q. et al. Fecal metabolomics and potential biomarkers for systemic lupus erythematosus. Front. Immunol. 10, 976 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

85. Narasimhan, R. et al. Serum metabolomic profiling predicts synovial gene expression in rheumatoid arthritis. Arthritis. Res. Ther. 20, 164 (2018).

86. Boasso, A., Herbeuval, J. P., Hardy, A. W., Winkler, C. & Shearer, G. M. Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells. Blood 105, 1574–1581 (2005).

    Article  CAS  PubMed  Google Scholar 

87. Wang, S. et al. Increased TTS abrogates IDO-mediated CD4(+) T cells suppression in patients with Graves’ disease. Endocrine 36, 119–125 (2009).

    Article  PubMed  CAS  Google Scholar 

88. Owens, D. K. et al. Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force Recommendation Statement. JAMA 321, 2203–2213 (2019).

    Article  PubMed  Google Scholar 

89. S, C. et al. Incorporation of lysyl-tRNA synthetase into human immunodeficiency virus type 1. J. Virol. 75, 5043–5048 (2001).

    Article  Google Scholar 

90. Javanbakht, H. et al. The interaction between HIV-1 Gag and human lysyl-tRNA synthetase during viral assembly. J. Biol. Chem. 278, 27644–27651 (2003).

    Article  CAS  PubMed  Google Scholar 

91. Kobbi, L., Octobre, G., Dias, J., Comisso, M. & Mirande, M. Association of mitochondrial Lysyl-tRNA synthetase with HIV-1 GagPol involves catalytic domain of the synthetase and transframe and integrase domains of Pol. J. Mol. Biol. 410, 875–886 (2011).

    Article  CAS  PubMed  Google Scholar 

92. Dewan, V., Wei, M., Kleiman, L. & Musier-Forsyth, K. Dual role for motif 1 residues of human lysyl-tRNA synthetase in dimerization and packaging into HIV-1. J. Biol. Chem. 287, 41955–41962 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

93. Halwani, R. et al. Cellular distribution of Lysyl-tRNA synthetase and its interaction with Gag during human immunodeficiency virus type 1 assembly. J. Virol. 78, 7553–7564 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

94. Duchon, A. A., St Gelais, C., Titkemeier, N., Hatterschide, J. & Wu, L. HIV-1 exploits a dynamic multi-aminoacyl-tRNA synthetase complex to enhance viral replication. J. Virol. https://doi.org/10.1128/jvi.01240-17 (2017).

95. Guo, F., Cen, S., Niu, M., Javanbakht, H. & Kleiman, L. Specific inhibition of the synthesis of human lysyl-tRNA synthetase results in decreases in tRNA(Lys) incorporation, tRNA(3)(Lys) annealing to viral RNA, and viral infectivity in human immunodeficiency virus type 1. J. Virol. 77, 9817–9822 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

96. Cen, S., Javanbakht, H., Niu, M. & Kleiman, L. Ability of wild-type and mutant lysyl-tRNA synthetase to facilitate tRNA(Lys) incorporation into human immunodeficiency virus type 1. J. Virol. 78, 1595–1601 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

97. Jones, C. P., Saadatmand, J., Kleiman, L. & Musier-Forsyth, K. Molecular mimicry of human tRNALys anti-codon domain by HIV-1 RNA genome facilitates tRNA primer annealing. RNA 19, 219–229 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

98. Liu, S., Comandur, R., Jones, C. P., Tsang, P. & Musier-Forsyth, K. Anticodon-like binding of the HIV-1 tRNA-like element to human lysyl-tRNA synthetase. RNA 22, 1828–1835 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

99. Comandur, R., Olson, E. D. & Musier-Forsyth, K. Conservation of tRNA mimicry in the 5’-untranslated region of distinct HIV-1 subtypes. RNA 23, 1850–1859 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

100. Clarke, P., Leser, J. S., Bowen, R. A. & Tyler, K. L. Virus-induced transcriptional changes in the brain include the differential expression of genes associated with interferon, apoptosis, interleukin 17 receptor A, and glutamate signaling as well as flavivirus-specific upregulation of tRNA synthetases. mBio 5, e00902–e00914 (2014).

     Article  PubMed  PubMed Central  CAS  Google Scholar 

101. Marquez-Jurado, S., Nogales, A., Zuniga, S., Enjuanes, L. & Almazan, F. Identification of a gamma interferon-activated inhibitor of translation-like RNA motif at the 3’ end of the transmissible gastroenteritis coronavirus genome modulating innate immune response. mBio 6, e00105 (2015).

     Article  PubMed  PubMed Central  CAS  Google Scholar 

102. Lee, E. Y. et al. Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity. Nat. Immunol. 17, 1252–1262 (2016).

     Article  CAS  PubMed  PubMed Central  Google Scholar 

103. Ellis, C. N. et al. Comparative proteomic analysis reveals activation of mucosal innate immune signaling pathways during cholera. Infect. Immun. 83, 1089–1103 (2015).

     Article  PubMed  PubMed Central  CAS  Google Scholar 

104. Duffy, F. J. et al. Immunometabolic signatures predict risk of progression to active tuberculosis and disease outcome. Front. Immunol. 10, 527 (2019).

     Article  CAS  PubMed  PubMed Central  Google Scholar 

105. Ahn, Y. H. et al. Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection. Nat. Microbiol. 2, 16191 (2016).

     Article  CAS  PubMed  Google Scholar 

106. Lee, M. S. et al. Shiga toxins trigger the secretion of Lysyl-tRNA synthetase to enhance proinflammatory responses. J. Microbiol. Biotechnol. 26, 432–439 (2016).

     Article  CAS  PubMed  Google Scholar 

107. Rycroft, J. A. et al. Activity of acetyltransferase toxins involved in Salmonella persister formation during macrophage infection. Nat. Commun. 9, 1993 (2018).

108. Wellman, T. L. et al. Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer. BMC Cancer 14, 620 (2014).

     Article  PubMed  PubMed Central  CAS  Google Scholar 

109. Kim, B. H. et al. Lysyl-tRNA synthetase (KRS) expression in gastric carcinoma and tumor-associated inflammation. Ann. Surg. Oncol. 21, 2020–2027 (2014).

     Article  PubMed  Google Scholar 

110. Kim, S. B., Kim, H. R., Park, M. C., Cho, S. & Goughnour, P. C. Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells. J. Cell. Biol. 216, 2201–2216 (2017).

111. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

     Article  CAS  PubMed  Google Scholar 

112. Kepp, O. et al. Lysyl tRNA synthetase is required for the translocation of calreticulin to the cell surface in immunogenic death. Cell Cycle 9, 3072–3077 (2010).

     Article  CAS  PubMed  Google Scholar 

113. Adam, I. & Dewi, D. L. Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation. Oncoimmunology 7, e1486353 (2018).

114. Nam, S. H. et al. Lysyl-tRNA synthetase-expressing colon spheroids induce M2 macrophage polarization to promote metastasis. J. Clin. Invest. 128, 5034–5055 (2018).

     Article  PubMed  PubMed Central  Google Scholar 

115. Park, M. C. et al. Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis. Proc. Natl Acad. Sci. USA 109, E640–E647 (2012).

     Article  CAS  PubMed  PubMed Central  Google Scholar 

116. Neenan, T. X., Burrier, R. E. & Kim, S. Biocon’s target factory. Nat. Biotechnol. 36, 791–797 (2018).

     Article  CAS  PubMed  Google Scholar 

117. Adachi, R. et al. Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline. Biochem. Biophys. Res. Commun. 488, 393–399 (2017).

     Article  CAS  PubMed  Google Scholar 

118. Keller, T. L. et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat. Chem. Biol. 8, 311–317 (2012).

     Article  CAS  PubMed  PubMed Central  Google Scholar 

119. Sundrud, M. S. et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324, 1334–1338 (2009).

     Article  CAS  PubMed  PubMed Central  Google Scholar 

120. Dewan, V. et al. Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction. ACS Chem. Biol. 7, 761–769 (2012).

     Article  CAS  PubMed  PubMed Central  Google Scholar 

121. Sciorati, C. et al. Exacerbation of murine experimental autoimmune myositis by Toll-like receptor 7/8. Arthritis Rheumatol. 70, 1276–1287 (2018).

     Article  CAS  PubMed  Google Scholar 

122. Sciorati, C. et al. Required role of apoptotic myogenic precursors and toll-like receptor stimulation for the establishment of autoimmune myositis in experimental murine models. Arthritis Rheumatol. 67, 809–822 (2015).

     Article  CAS  PubMed  Google Scholar 

123. Ishikawa, Y. et al. Functional engraftment of human peripheral T and B cells and sustained production of autoantibodies in NOD/LtSzscid/IL-2Rgamma(-/-) mice. Eur. J. Immunol. 44, 3453–3463 (2014).

     Article  CAS  PubMed  Google Scholar 

Page 2

1. ARSs aminoacyl-tRNA synthetases, ASSD antisynthetase syndrome, HisRS histidyl-tRNA synthetase, AsnRS asparaginyl-tRNA synthetase, CCR3 CC chemokine receptor 3, MyD88 multiple myeloid differentiation primary response gene 88, TLR Toll-like receptor, NK cells natural killer cells, PBMC peripheral blood mononuclear cell, APCs antigen-presenting cells, DCs dendritic cells, WRS tryptophanyl-tRNA synthetase, IDO indoleamine-2,3-dioxygenase, KRS lysyl-tRNA synthetase, HIV-1 human immunodeficiency virus-1, MSC multisynthetase complex, JEV Japanese encephalitis virus, WNV West Nile virus, EPRS glutamyl-prolyl-tRNA synthetase, RRS arginyl-tRNA synthetase, TGEV transmissible gastroenteritis coronavirus, GAIT gamma interferon-activated inhibitor of translation, PCBP2 poly(rC)-binding protein 2, MAVS mitochondrial antiviral signaling protein, MD2 myeloid differentiation factor 2, ThrRS threonyl-tRNA synthetase, VEGF vascular endothelial growth factor, CRT calreticulin, GCN2 general control non-derepressible-2, eIF2α eukaryotic translation initiation factor 2α, ATF4 activating transcription factor 4, IFN-γ interferon-γ, CAFs cancer-associated fibroblasts, GRS glycyl-tRNA synthetase, ERK extracellular signal-regulated kinase.