Induction of Angiogenesis by a Fragment of Human Tyrosyl-tRNA Synthetase

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.Previous work on human tyrosyl-tRNA synthetase (TyrRS)

Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses

“…1a). On the other hand, human cytoplasmic TyrRS has a C-terminal extension in the form of an EMAPII domain that undergoes proteolytic processing to reveal a host module more similar in size to PfTyrRS [9][10][11][12][13] (Fig. 1a).…”

“…2e). In full-length cytoplasmic HsTyrRS, the ELR motif is buried under the C-terminal EMAPII domain, and this motif is exposed after proteolytic cleavage [9][10][11][12][13] . In contrast, the PfTyrRS ELR motif is exposed in three-dimensional space and does not require processing for its surface display.…”

“…We tested this hypothesis by incubating mouse and human macrophage cell lines with recombinant wild-type PfTyrRS, with a mutant ELR/AAA-PfTyrRS, with lipopolysaccharide (LPS) (as positive control), with media alone and PfDTD (last two as negative controls). In these studies, the amounts of PfTyrRS used were in nanomolar (nM) concentration ranges, similar to amounts used in studies with human mini-TyrRS [9][10][11][12][13] . Time kinetic analysis using ELISA revealed maximal production of the inflammatory cytokines TNF-α, IL-6 and IL-1(α and β) within 6 hours of culture (Tukey's test-P < 0.001) (Fig.…”

Tumor endothelial cell tube formation model for determining anti-angiogenic activity of a tRNA synthetase cytokine

“…Tryptophanyl-tRNA synthetase (TrpRS) is a prime example of a synthetase procytokine. Through alternative splicing or natural proteolysis, fragments known as mini-TrpRS (alternative splicing), or the closely similar T2-TrpRS (natural proteolysis), are potent anti-angiogenic factors that, after exocytosis, bind to cell surface VE-cadherin and trigger arrest of neo-angiogenesis through the Akt signaling pathway (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Do Aminoacyl-tRNA synthetases have biological functions other than in protein biosynthesis?

“…YRS is secreted and processed by elastase into an N-terminal fragment, mini-YRS, which is pro-angiogenic, and a C-terminal fragment that stimulates immune cells to migrate and produce TNFa, tissue factor, and myeloperoxidase (17). The pro-angiogenic activity of mini-YRS resembles that of CXC-chemokines such as interleukin 8, and depends on the three amino acid ELR motif located within the Rossmann-fold catalytic domain (17,18). In contrast to YRS, two truncated isoforms of tryptophanyltRNA synthetase (WRS), mini-WRS and T2 WRS have potent anti-angiogenic activity (19 -21).…”