Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Immunology, and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
J Immunol. 2021 Jul 1;207(1):296-307. doi: 10.4049/jimmunol.2001167. Epub 2021 Jun 28.
Neddylation, a posttranslational modification in which NEDD8 is covalently attached to target proteins, has emerged as an endogenous regulator of innate immunity. However, the role of neddylation in methicillin-resistant (MRSA) infection remains unknown. In this study, we found that neddylation was activated after MRSA infection in vivo and in vitro. Inhibition of neddylation with MLN4924 promoted injury of liver and kidneys in C57BL/6 mice with MRSA bloodstream infection and increased mortality. Blockade of neddylation, either pharmacologically (MLN4924, DI591) or through the use of small interfering RNA, inhibited Cullin3 neddylation and promoted Nrf2 accumulation, thus reducing reactive oxygen species (ROS) induction and bacterial killing ability in mouse peritoneal macrophages. In summary, our findings suggest that activation of neddylation in macrophages plays a critical protective role against MRSA infection by increasing ROS production, partially by signaling through the NEDD8-Cullin3-Nrf2-ROS axis. Furthermore, our results may provide a new non-antibiotic treatment strategy for MRSA infection through targeting of neddylation.
Neddylation 是一种将 NEDD8 共价连接到靶蛋白上的翻译后修饰过程，它已成为先天免疫的内源性调节剂。然而，Neddylation 在耐甲氧西林金黄色葡萄球菌（MRSA）感染中的作用尚不清楚。在本研究中，我们发现 Neddylation 在体内和体外 MRSA 感染后被激活。用 MLN4924 抑制 Neddylation 可促进 C57BL/6 小鼠耐甲氧西林金黄色葡萄球菌菌血症中的肝和肾损伤，并增加死亡率。通过药理学（MLN4924、DI591）或使用小干扰 RNA 阻断 Neddylation，抑制 Cullin3 Neddylation 并促进 Nrf2 积累，从而减少小鼠腹腔巨噬细胞中活性氧（ROS）的诱导和杀菌能力。总之，我们的研究结果表明，巨噬细胞中 Neddylation 的激活通过增加 ROS 产生，部分通过 NEDD8-Cullin3-Nrf2-ROS 轴信号传导，在对抗 MRSA 感染中发挥关键的保护作用。此外，我们的结果可能通过靶向 Neddylation 为 MRSA 感染提供一种新的非抗生素治疗策略。
