College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
College of Korean Medicine, Daejeon University, Daejeon 34520, Republic of Korea.
Nat Microbiol. 2016 Oct 17;2:16191. doi: 10.1038/nmicrobiol.2016.191.
The N-terminal truncated form of a protein synthesis enzyme, tryptophanyl-tRNA synthetase (mini-WRS), is secreted as an angiostatic ligand. However, the secretion and function of the full-length WRS (FL-WRS) remain unknown. Here, we 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 sepsis patients, but not in those with sterile inflammation. FL-WRS was secreted from monocytes and directly bound to macrophages via a toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to induce phagocytosis and chemokine production. Administration of FL-WRS into Salmonella typhimurium-infected mice reduced the levels of bacteria and improved mouse survival, whereas its titration with the specific antibody aggravated the infection. 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 now suggested. Based on these results, secretion of FL-WRS appears to work as a primary defence system against infection, acting before full activation of innate immunity.
一种蛋白质合成酶，色氨酰-tRNA 合成酶（mini-WRS）的 N 端截短形式作为血管生成抑制配体被分泌。然而，全长 WRS（FL-WRS）的分泌和功能仍不清楚。在这里，我们报告说，FL-WRS 而不是 mini-WRS，在病原体感染时会迅速被分泌以启动先天免疫。败血症患者血液中的 FL-WRS 水平升高，但无菌性炎症患者则没有。FL-WRS 从单核细胞中分泌出来，并通过 Toll 样受体 4（TLR4）-髓样分化因子 2（MD2）复合物直接与巨噬细胞结合，诱导吞噬作用和趋化因子的产生。将 FL-WRS 给药于鼠伤寒沙门氏菌感染的小鼠中，可降低细菌水平并提高小鼠的存活率，而用特异性抗体滴定则加重了感染。WRS 的 154 个氨基酸的 N 端真核生物特异性肽足以重现 FL-WRS 的活性，并且现在提出了其与 TLR4-MD2 的相互作用模式。基于这些结果，FL-WRS 的分泌似乎作为一种针对感染的主要防御系统发挥作用，在先天免疫的完全激活之前发挥作用。
