Cheng Qiao, Wang Dong, Lai Xiaoxuan, Liu Yin, Zuo Yibo, Zhang Wenli, Lei Lei, Chen Jia, Liu Hong, Wang Ying, Liu Haiyan, Zheng Hui, Wu Depei, Xu Yang
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
Blood. 2023 Mar 23;141(12):1474-1488. doi: 10.1182/blood.2022017201.
Disorders of the ubiquitin-proteasome system (UPS) are known to influence the incidence and mortality of various diseases. It remains largely unknown whether and how the UPS affects the onset and progression of acute graft-verus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study demonstrated that the deubiquitinase OTUD1 is an essential regulator of aGVHD. Activation of CD4+ T cells after allo-HSCT, elevated the protein levels of OTUD1, which in turn interacted with the Notch2-ICD (NICD) to cleave the ubiquitin of NICD at the K1770 site, thereby inducing NICD protein accumulations in T cells. OTUD1-driven NICD signaling promoted the differentiation and functions of Th1 and Th17 cells and amplified the cascade of aGVHD. Moreover, by screening a FDA-approved drugs library the study identified dapagliflozin as an inhibitor targeting the OTUD1/NICD axis. Dapagliflozin administration significantly prolonged the survival of aGVHD mice. This study characterized a previously unknown role of OTUD1 in T cell-mediated allogeneic responses and provided a promising therapeutic strategy to target OTUD1 for the alleviation of aGVHD.
已知泛素-蛋白酶体系统（UPS）功能紊乱会影响多种疾病的发病率和死亡率。异基因造血干细胞移植（allo-HSCT）后，UPS是否以及如何影响急性移植物抗宿主病（aGVHD）的发生和发展，目前仍不清楚。本研究表明，去泛素化酶OTUD1是aGVHD的关键调节因子。allo-HSCT后CD4+T细胞激活，使OTUD1蛋白水平升高，进而与Notch2细胞内结构域（NICD）相互作用，在K1770位点切割NICD的泛素，从而诱导T细胞中NICD蛋白积累。OTUD1驱动的NICD信号促进Th1和Th17细胞的分化及功能，放大aGVHD级联反应。此外，通过筛选美国食品药品监督管理局（FDA）批准的药物库，该研究确定达格列净是靶向OTUD1/NICD轴的抑制剂。给予达格列净可显著延长aGVHD小鼠的生存期。本研究明确了OTUD1在T细胞介导的同种异体反应中一个此前未知的作用，并为靶向OTUD1缓解aGVHD提供了一种有前景的治疗策略。
