Gu Wangpeng, Zhang Jia, Li Qing, Zhang Yaguang, Lin Xuan, Wu Bingbing, Yin Qi, Sun Jinqiao, Lu Yulan, Sun Xiaoyu, Jia Caiwei, Li Chuanyin, Zhang Yu, Wang Meng, Yin Xidi, Wang Su, Xu Jiefang, Wang Ran, Zhu Songling, Cheng Shipeng, Chen Shuangfeng, Liu Lian, Zhu Lin, Yan Chenghua, Yi Chunyan, Li Xuezhen, Lian Qiaoshi, Lin Guomei, Ling Zhiyang, Ma Liyan, Zhou Min, Xiao Kuanlin, Wei Haiming, Hu Ronggui, Zhou Wenhao, Ye Lilin, Wang Haikun, Li Jinsong, Sun Bing
Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Cell Discov. 2023 Aug 1;9(1):82. doi: 10.1038/s41421-023-00561-z.
The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FIN (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (T) cell development and antibody production. The effects of Trim37 on T cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of T cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.
由TRIM37基因功能丧失变异引起的穆利布雷（肌肉-肝脏-脑-眼）矮小症是一种常染色体隐性疾病，其特征为严重生长发育迟缓及缩窄性心包炎。这些患者还易患严重呼吸道感染，死亡率也较高。在此，我们发现TRIM37变异与反复感染有关。Trim37 FIN（穆利布雷矮小症患者的代表性变异）和Trim37基因敲除小鼠易感染流感病毒。这些小鼠在滤泡辅助性T细胞发育和抗体产生方面存在缺陷。Trim37对T细胞分化的影响依赖于其E3连接酶活性，该活性催化Bcl6的K27/29连接的多聚泛素化及其MATH结构域介导的与Bcl6的相互作用，从而保护Bcl6不被蛋白酶体介导的降解。总体而言，这些发现突出了Trim37-Bcl6轴在控制T细胞发育和高亲和力抗体产生中的重要性，并进一步揭示了穆利布雷矮小症反复呼吸道感染的免疫机制。
