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

A Corrigendum to this article was published on 23 January 2017

Abstract

The N-terminal truncated form of a protein synthesis enzyme, tryptophanyl-tRNA synthetase (mini-WRS), is secreted as an angiostatic ligand. However, the secretion and function of the full-length WRS (FL-WRS) remain unknown. Here, we report that the FL-WRS, but not mini-WRS, is rapidly secreted upon pathogen infection to prime innate immunity. Blood levels of FL-WRS were increased in sepsis patients, but not in those with sterile inflammation. FL-WRS was secreted from monocytes and directly bound to macrophages via a toll-like receptor 4 (TLR4)–myeloid differentiation factor 2 (MD2) complex to induce phagocytosis and chemokine production. Administration of FL-WRS into Salmonella typhimurium-infected mice reduced the levels of bacteria and improved mouse survival, whereas its titration with the specific antibody aggravated the infection. The N-terminal 154-amino-acid eukaryote-specific peptide of WRS was sufficient to recapitulate FL-WRS activity and its interaction mode with TLR4–MD2 is now suggested. Based on these results, secretion of FL-WRS appears to work as a primary defence system against infection, acting before full activation of innate immunity.

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Figure 1: Serum level of WRS in patients with sepsis and sterile inflammatory immune disorders.
Figure 2: WRS secretion from monocytes prior to TNF-α following infection.
Figure 3: FL-WRS, but not mini-WRS, activates macrophages to prime innate immune responses.
Figure 4: FL-WRS protects bacteria-infected mice from lethality.
Figure 5: Role of TLR4–MD2 and TLR2 in FL-WRS activation of innate immune responses.
Figure 6: FL-WRS directly interacts with TLR4–MD2.

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Acknowledgements

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2010-0012505), Bio-Synergy/research Project (2014M3A9C4066465) and Global Frontier Project grants nos. NRF-M3A6A4-2010-0029785 and 2015M3A6A4065732 of the National Research Foundation funded by the Ministry of Science, ICT & Future Planning (MSIP) of Korea.

Author information

Authors and Affiliations

Authors

Contributions

Co-first authors Y.H.A. and S.P. performed the experiments and analysed the data. J.J.C., B.-K.P., K.H.R., E.K., S.A., K.-S.I., N.H.K., H.S., B.W.H., P.K., J.-Y.L. and Y.J. performed experiments. C.-H.L. and J.S.L. provided knockout animals. M.-L.C., S.-H.P., K.P., H.J.P., J.-H.L., J.-W.P. and J.W.H. provided sera and discussed clinical data. M.J. and S.K. designed the experiments, supervised the research and wrote the paper. All authors approved the final manuscript.

Corresponding authors

Correspondence to Mirim Jin or Sunghoon Kim.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures 1–9, Supplementary Tables 1 and 2, legends for Supplementary Videos 1–6 (PDF 1599 kb)

Supplementary Video 1

Infiltration of neutrophil and monocyte/macraophage 30 min after PBS injection. (AVI 8931 kb)

Supplementary Video 2

Infiltration of neutrophil and monocyte/macraophage 4 hr after PBS injection. (AVI 11085 kb)

Supplementary Video 3

Infiltration of neutrophil and monocyte/macraophage 30 min after FL-WRS injection. (AVI 8204 kb)

Supplementary Video 4

Infiltration of neutrophil and monocyte/macraophage 4 hr after FL-WRS injection. (AVI 6213 kb)

Supplementary Video 5

Infiltration of neutrophil and monocyte/macraophage 30 min after mini-WRS 23 injection. (AVI 13234 kb)

Supplementary Video 6

Infiltration of neutrophil and monocyte/macraophage 4 hr after mini-WRS injection. (AVI 4830 kb)

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Ahn, Y., Park, S., Choi, J. et al. Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection. Nat Microbiol 2, 16191 (2017). https://doi.org/10.1038/nmicrobiol.2016.191

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