PDF(Pubmed)
Abstract：
Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING\'s palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.
摘要：
金黄色葡萄球菌（S。金黄色葡萄球菌）可以通过在感染细胞内持续存在来逃避抗生素和宿主免疫防御。这里,我们证明在受感染的宿主细胞中，金黄色葡萄球菌VII型分泌系统（T7SS）胞外蛋白B（EsxB）与干扰素基因（STING）蛋白的刺激因子相互作用，并在感染早期抑制巨噬细胞的炎症防御机制。EsxB与STING的结合破坏了EsxB在赖氨酸33处的K48连接的泛素化,从而防止了EsxB降解。此外，EsxB-STING结合似乎中断了2种重要调节蛋白与STING的相互作用:含天冬氨酸-组氨酸-组氨酸-半胱氨酸结构域的蛋白3(DHHC3)和TNF受体相关因子6。这种对STING相互作用的持续双重抑制使巨噬细胞的细胞内促炎途径失调，抑制STING在半胱氨酸91处的棕榈酰化及其在赖氨酸83处的K63连接的泛素化。这些发现揭示了金黄色葡萄球菌T7SS在细胞内巨噬细胞感染期间的免疫逃避机制，这对开发有效的免疫调节剂来对抗金黄色葡萄球菌感染具有重要意义。
