Studies on the Role of Tryptophanyl-tRNA Synthetase in Early Defense against Pathogenic Infection

Abstract

Tryptophanyl-tRNA synthetase (WRS) is a member of aminoacyl-tRNA synthetases (ARSs) and is an essential enzyme in protein synthesis. Recently, it is well known that these ARSs exhibit various biological functions in addition to their essential functions. Mini-WRSs lacking an extra N-terminal domain have been shown to inhibit angiogenesis. However, the secretion and function of the full-length WRS (FL-WRS) remain unknown. Here I 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 the sepsis patients compared with healthy subjects, but not in those with sterile inflammation. FL-WRS, which was present in cytoplasm of human monocytes, was secreted in a few minutes when pathogenic infectious agents (bacteria, viruses, fungi, etc.) invaded. The secreted FL-WRS, in combination with the TLR4-MD2 complex, increased the phagocytosis of macrophages and, at the same time, induces neutrophil infiltration through chemokine secretion, thereby eradicating the infectious agent initially. 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 suggested. Administration of FL-WRS into Salmonella typhimurium–infected mice reduced the bacteria counts in tissues and improved mouse survival, whereas its titration with the specific antibody aggravated the infection. These results suggest that FL-WRS acts as an early defense system to prevent pathogens from infesting at the initial stage of infection.