Anti-apoptotic HAX-1 suppresses cell apoptosis by promoting c-Abl kinase-involved ROS clearance |
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Authors: | Qincai Dong Dapei Li Huailong Zhao Xun Zhang Yue Liu Yong Hu Yi Yao Lin Zhu Guang-Fei Wang Hainan Liu Ting Gao Xiayang Niu Tong Zheng Caiwei Song Di Wang Yu Bai Jing Jin Zijing Liu Yanwen Jin Ping Li Cheng Cao Xuan Liu |
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Affiliation: | 1.Beijing Institute of Biotechnology, 27 Taiping Rd, Haidian District, 100850 Beijing, China ;2.Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China ;3.Suzhou Institute of Systems Medicine, 215123 Suzhou, China ;4.Jinan Center for Disease Control and Prevention, 250021 Jinan, Shandong China ;5.Institute of Health Sciences, Anhui University, 230601 Hefei, China |
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Abstract: | The anti-apoptotic protein HAX-1 has been proposed to modulate mitochondrial membrane potential, calcium signaling and actin remodeling. HAX-1 mutation or deficiency results in severe congenital neutropenia (SCN), loss of lymphocytes and neurological impairments by largely unknown mechanisms. Here, we demonstrate that the activation of c-Abl kinase in response to oxidative or genotoxic stress is dependent on HAX-1 association. Cellular reactive oxygen species (ROS) accumulation is inhibited by HAX-1-dependent c-Abl activation, which greatly contributes to the antiapoptotic role of HAX-1 in stress. HAX-1 (Q190X), a loss-of-function mutant responsible for SCN, fails to bind with and activate c-Abl, leading to dysregulated cellular ROS levels, damaged mitochondrial membrane potential and eventually apoptosis. The extensive apoptosis of lymphocytes and neurons in Hax-1-deficient mice could also be remarkably suppressed by c-Abl activation. These findings underline the important roles of ROS clearance in HAX-1-mediated anti-apoptosis by c-Abl kinase activation, providing new insight into the pathology and treatment of HAX-1-related hereditary disease or tumorigenesis.Subject terms: Apoptosis, Kinases |
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