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Abstract
The first step of protein synthesis is catalyzed by aminoacyl-tRNA synthetases. In addition, certain mammalian tRNA synthetases link protein synthesis to cytokine signaling pathways. In particular, human tyrosyl-tRNA synthetase (TyrRS) can be split by proteolysis into two fragments having distinct cytokine activities. One of the TyrRS fragments (mini TyrRS) contains features identical to those in CXC chemokines (like interleukin-8) that also act as angiogenic factors. Here mini TyrRS (but not full-length TyrRS) is shown to stimulate chemotaxis of endothelial cells in vitro and stimulate angiogenesis in each of two in vivo animal models. The angiogenic activity of mini TyrRS can be opposed by anti-angiogenic chemokines like IP-10. Thus, a biological fragment of human tyrosyl-tRNA synthetase links protein synthesis to regulation of angiogenesis.
Highlights
From ‡The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology and the ¶Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037
Human Umbilical Vein Endothelial Cell (HUVEC) Chemotaxis in Response to Mini TyrRS—In earlier experiments, we found that mini TyrRS stimulated polymorphonuclear leukocytes (PMNs) migration and that an ELR motif within human mini TyrRS was essential for the cytokine-like activity [1, 3]
Several functional similarities between human mini TyrRS and IL-8 suggest a common mechanism of action
Summary
One of the TyrRS fragments (mini TyrRS) contains features identical to those in CXC chemokines (like interleukin-8) that act as angiogenic factors. 1 The abbreviations used are: TyrRS, tyrosyl-tRNA synthetase; Cdomain, C-terminal domain; PMN, polymorphonuclear leukocyte; IL, interleukin; HUVEC, human umbilical vein endothelial cell; VEGF, vascular endothelial growth factor; CAM, chicken chorioallantoic membrane; PBS, phosphate-buffered saline; GSL-B4, Griffonia (Bandeiraea) simplicifolia isolectin B4; TrpRS, tryptophanyl-tRNA synthetase. The N-terminal domain (mini TyrRS), containing the Rossmann nucleotide-binding fold common to the 10 class I tRNA synthetases, induced directed migration of PMN cells with a bell-shaped concentration dependence like that of the CXC chemokine interleukin-8 (IL-8).
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