Clinical Biological Resource Bank and Clinical Lab, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
Pediatric Immunity and Healthcare Biomedical Co., Ltd, Guangzhou, China.
Nat Cardiovasc Res. 2023 Aug;2(8):778-792. doi: 10.1038/s44161-023-00314-x. Epub 2023 Aug 11.
Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discovered that nitric oxide signaling promotes TRIM21-mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore-forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LC3-interacting region (LIR) motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21 and Nos2 or reconstituted with the East-Asian-specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.
自噬是一种主要的质量控制途径，可清除不需要的或功能失调的线粒体，并在血管健康中发挥重要作用。在这里，我们发现川崎病（KD）患儿的 MCM8 表达明显降低，这些患儿发生了冠状动脉瘤。从机制上讲，我们发现一氧化氮信号促进 TRIM21 介导的 MCM8 泛素化，破坏其与 MCM9 的相互作用，并促进其胞质输出。在细胞质中，MCM8 重新定位到线粒体孔形成蛋白，并通过 TRIM21 促进其泛素化。此外，MCM8 通过其 LC3 相互作用区域（LIR）基序直接招募 LC3 并启动自噬。这通过 cGAS 和 STING 抑制线粒体 DNA 介导的 I 型干扰素的激活。Mcm8、Trim21 和 Nos2 缺失的小鼠或用东亚特异性 MCM8-P276 变体重建的小鼠在干酪乳杆菌提取物诱导的 KD 模型中发展出更严重的冠状动脉血管病变。总的来说，这些数据表明 MCM8 在 KD 环境中保护血管健康。
