Li Yanfeng, Xie Qingqing, Yang Luyu, Jiang Qian, Liu Zhiping, Gao Chengjiang, Qi Xiaopeng, Xu Tao
Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
School of Nursing; Gannan Medical UniversityGanzhou, Jiangxi, China.
PLoS Pathog. 2025 Jul 7;21(7):e1013333. doi: 10.1371/journal.ppat.1013333. eCollection 2025 Jul.
RNF213 is the first identified susceptibility gene for moyamoya disease, and the encoded protein was recently recognized as a key antimicrobial protein. However, the function of RNF213 in host defense against brain infection remains unclear. Here, we show that increased expression of Rnf213 is significantly regulated by interferon alpha/beta receptor (IFNAR) signaling during bacterial infection and ligand stimulation. RNF213 deficiency impairs type I interferon (IFN-I) production and decreases the expression of interferon-stimulated genes (ISGs) in response to IFN-β stimulation and Acinetobacter baumannii infection. Mechanistically, RNF213 interacts with TRAF3 and mediates the K27-linked polyubiquitination of TRAF3 at K160. RNF213 regulates the expression of the endothelial tight junction-related genes Claudin-5, Occludin, and Pecam1 via IFN-I signaling. Furthermore, RNF213 deficiency in nonimmune cells increases blood‒brain barrier (BBB) disruption and the bacterial load in the brain parenchyma in response to A. baumannii infection due to impaired IFN-I signaling. Thus, RNF213 mediates BBB integrity by targeting TRAF3 for the regulation of IFN-I signaling against bacterial brain infection. Our study principally provides a deeper understanding of the function of RNF213 and reveals potential therapeutic targets against bacterial brain infection and moyamoya disease.
RNF213是首个被鉴定出的烟雾病易感基因，其编码的蛋白质最近被认为是一种关键的抗菌蛋白。然而，RNF213在宿主抵抗脑部感染中的功能仍不清楚。在此，我们表明，在细菌感染和配体刺激过程中，Rnf213的表达增加受到干扰素α/β受体（IFNAR）信号的显著调控。RNF213缺陷会损害I型干扰素（IFN-I）的产生，并降低在响应IFN-β刺激和鲍曼不动杆菌感染时干扰素刺激基因（ISG）的表达。从机制上讲，RNF213与TRAF3相互作用，并介导TRAF3在K160处发生K27连接的多聚泛素化。RNF213通过IFN-I信号调节内皮紧密连接相关基因Claudin-5、Occludin和Pecam1的表达。此外，由于IFN-I信号受损，非免疫细胞中的RNF213缺陷会增加血脑屏障（BBB）的破坏以及在响应鲍曼不动杆菌感染时脑实质中的细菌载量。因此，RNF213通过靶向TRAF3来调节针对细菌性脑部感染的IFN-I信号，从而介导血脑屏障的完整性。我们的研究主要提供了对RNF213功能的更深入理解，并揭示了针对细菌性脑部感染和烟雾病的潜在治疗靶点。
