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

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Authors
안영하
Advisor
김성훈
Major
약학대학 약학과
Issue Date
2017-02
Publisher
서울대학교 대학원
Keywords
secreted full-length tryptophanyl-tRNA synthetase (FL-WRS)sepsisinfectioninnate immunityendogenous ligandTLR4
Description
학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2017. 2. 김성훈.
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.
Language
Korean
URI
https://hdl.handle.net/10371/120151
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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