National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
Department of Medical Engineering, Xinqiao Hospital, Third Military Medical University, Chongqing 400038, China.
Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2402764121. doi: 10.1073/pnas.2402764121. Epub 2024 May 21.
() can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, 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 T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat infections.
()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。在这里，我们证明在受感染的宿主细胞中，VII 型分泌系统（T7SS）细胞外蛋白 B（EsxB）与干扰素基因刺激物（STING）蛋白相互作用，并在早期感染期间抑制巨噬细胞的炎症防御机制。EsxB 与 STING 的结合破坏了 EsxB 赖氨酸 33 上的 K48 连接泛素化，从而阻止 EsxB 降解。此外，EsxB-STING 结合似乎中断了 2 种重要的调节蛋白与 STING 的相互作用：天冬氨酸-组氨酸-组氨酸-半胱氨酸结构域蛋白 3（DHHC3）和肿瘤坏死因子受体相关因子 6。这种持续的 STING 相互作用的双重抑制使巨噬细胞中的细胞内促炎途径失调，抑制 STING 在半胱氨酸 91 上的棕榈酰化和在赖氨酸 83 上的 K63 连接泛素化。这些发现揭示了 T7SS 在细胞内巨噬细胞感染期间的一种免疫逃避机制，这对于开发有效的免疫调节剂来对抗 感染具有重要意义。
