Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

doi:10.1073/pnas.0500226102

Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

National Creative Research Initiatives Center for ARS Network, College of Pharmacy, Seoul National University, Seoul 151-742, Korea

Edited by Paul R. Schimmel, The Scripps Research Institute, La Jolla, CA, and approved March 22, 2005 (received for review January 11, 2005)

Abstract

Although aminoacyl-tRNA synthetases (ARSs) are essential for protein synthesis, they also function as regulators and signaling molecules in diverse biological processes. Here, we screened 11 different human ARSs to identify the enzyme that is secreted as a signaling molecule. Among them, we found that lysyl-tRNA synthetase (KRS) was secreted from intact human cells, and its secretion was induced by TNF-α. The secreted KRS bound to macrophages and peripheral blood mononuclear cells to enhance the TNF-α production and their migration. The mitogen-activated protein kinases, extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, and Gαi were determined to be involved in the signal transduction triggered by KRS. All of these activities demonstrate that human KRS may work as a previously uncharacterized signaling molecule, inducing immune response through the activation of monocyte/macrophages.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: sungkim{at}snu.ac.kr.
↵ * S.G.P. and H.J.K. contributed equally to the work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ARS, aminoacyl-tRNA synthetase; ERK, extracellular signal-regulated kinase; Gαi, inhibitory G protein; KRS, lysyl-tRNA synthetase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; PBMC, peripheral blood mononuclear cell; WRS, tryptophanyl-tRNA synthetase.