Institute of Experimental Internal Medicine, Medical Faculty, Otto Von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
Cell Mol Life Sci. 2022 Aug 1;79(8):461. doi: 10.1007/s00018-022-04489-7.
The human pathogen Helicobacter pylori represents a risk factor for the development of gastric diseases including cancer. The H. pylori-induced transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is involved in the pro-inflammatory response and cell survival in the gastric mucosa, and represents a trailblazer of gastric pathophysiology. Termination of nuclear NF-κB heterodimer RelA/p50 activity is regulated by the ubiquitin-RING-ligase complex elongin-cullin-suppressor of cytokine signalling 1 (ECS), which leads to K48-ubiquitinylation and degradation of RelA. We found that deubiquitinylase (DUB) ubiquitin specific protease 48 (USP48), which interacts with the COP9 signalosome (CSN) subunit CSN1, stabilises RelA by deubiquitinylation and thereby promotes the transcriptional activity of RelA to prolong de novo synthesis of DUB A20 in H. pylori infection. An important role of A20 is the suppression of caspase-8 activity and apoptotic cell death. USP48 thus enhances the activity of A20 to reduce apoptotic cell death in cells infected with H. pylori. Our results, therefore, define a synergistic mechanism by which USP48 and A20 regulate RelA and apoptotic cell death in H. pylori infection.
人类病原体幽门螺杆菌是导致包括癌症在内的胃部疾病的危险因素。幽门螺杆菌诱导的转录因子核因子κB 轻链增强子的 B 细胞（NF-κB）参与胃黏膜的炎症反应和细胞存活，是胃生理病理学的先驱。核 NF-κB 异二聚体 RelA/p50 活性的终止受泛素-RING-连接酶复合物 elongin-cullin-细胞因子信号转导抑制因子 1（ECS）的调节，导致 RelA 的 K48-泛素化和降解。我们发现，去泛素酶（DUB）泛素特异性蛋白酶 48（USP48）与 COP9 信号体（CSN）亚基 CSN1 相互作用，通过去泛素化稳定 RelA，从而促进 RelA 的转录活性，延长幽门螺杆菌感染中新合成的 DUB A20。A20 的一个重要作用是抑制半胱天冬酶-8 的活性和细胞凋亡。因此，USP48 增强了 A20 的活性，减少了感染幽门螺杆菌的细胞的凋亡。因此，我们的研究结果定义了 USP48 和 A20 在幽门螺杆菌感染中调节 RelA 和细胞凋亡的协同机制。
