【《Nat Rev Cardiol》——MCM8在川崎病发展过程中保护血管健康】
研究人员发现，MCM8和TRIM21通过促进一氧化氮（NO）依赖性线粒体自噬在血管健康中发挥关键作用，而MCM8的东亚特异性P276变体诱导线粒体自噬的能力降低，从而导致更高的KD发生率。

【题目】 MCM8介导的线粒体自噬在川崎病小鼠模型中响应一氧化氮信号，保护血管健康

【摘要】 线粒体自噬是一种主要的质控途径，可清除不需要或功能失调的线粒体，在血管健康中发挥着至关重要的作用。在这里，我们在发生冠状动脉瘤的川崎病（KD）儿童体内观察到了微小染色体维持蛋白8（MCM8）表达量明显降低。机制上，我们发现NO信号促进了E3泛素连接酶TRIM21介导的MCM8泛素化，从而破坏了MCM8与MCM9的相互作用，并促进了其在胞浆中的输出。在胞浆中，MCM8迁移至线粒体成孔蛋白上，并通过TRIM21促进其泛素化。此外，MCM8还通过其LC3结合区（LIR）基序直接招募LC3，并启动线粒体自噬。这就抑制了线粒体DNA通过cGAS-STING介导的I型干扰素激活。在乳酸杆菌提取物诱导的KD模型中，缺乏Mcm8、Trim21和一氧化氮合成酶2(Nos2)或用东亚特异性MCM8-P276突变体小鼠会出现更严重的冠状动脉血管病变。总之，这些数据表明，MCM8能在KD环境中保护血管健康。

英文原文

[Report] Researchers discovered that MCM8 and the E3 ubiquitin ligase TRIM21 play a critical role in vascular health by promoting NO-dependent mitophagy and that the East-Asian-specific P276 variant has reduced ability to induce mitophagy, that results in higher KD incidences.

[Title] MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease

[Authors] Meng Lin, Huifang Xian, Zhanghua Chen, Shang Wang, Ming Liu, Weiwei Liang, Qin Tang, Yao Liu, Wanming Huang, Di Che, Caiqin Guo, Elina Idiiatullina, Rongli Fang, Mahmoud AL-Azab, Jingjie Chang, Rongze Wang, Xiaojun Li, Xiaoyu Zuo, Yan Zhang, Jincun Zhao, Yaping Tang, Shouheng Jin, Zhengjie He, Du Feng, Liwei Lu, Kang Zhang, Yan Wu, Fan Bai, Andrew M. Lew, Jun Cui, Yuzhang Wu, Xiaoqiong Gu & Yuxia Zhang

[Abstract] 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.

原文链接

http://t.cn/A6Oa3YRB