Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 310036, China.
Cell Death Dis. 2023 Jan 30;14(1):71. doi: 10.1038/s41419-023-05559-9.
Excessive protein synthesis upon enhanced cell proliferation frequently results in an increase of unfolded or misfolded proteins. During hematopoietic regeneration, to replenish the hematopoietic system, hematopoietic stem cells (HSCs) are activated and undergo a rapid proliferation. But how the activated HSCs respond to the proliferation pressure is still ambiguous; The proper control of the functional reservoir in the activated HSCs remains poorly understood. Here, we show a significant upregulation of EVA1A protein associated with the increase of ER stress during hematopoietic regeneration. Deletion of Eva1a significantly enhances the regeneration capacity of HSCs by inhibiting the ER stress-induced apoptosis. Mechanistically, the expression of EVA1A protein was upregulated by CHOP, and thereby promoted the ER-mitochondria interlinking via MCL1, which resulted in mitochondria-mediated apoptosis. These findings reveal a pathway for ER stress responses of HSCs by the EVA1A mediated apoptosis, which play an important role in HSCs regeneration.
在细胞增殖增强时，蛋白质合成过度通常会导致未折叠或错误折叠的蛋白质增加。在造血再生过程中，为了补充造血系统，造血干细胞 (HSCs) 被激活并经历快速增殖。但是，激活的 HSCs 如何应对增殖压力仍不清楚；激活的 HSCs 中功能性储备的适当控制仍知之甚少。在这里，我们发现在造血再生过程中与 ER 应激增加相关的 EVA1A 蛋白显著上调。Eva1a 的缺失通过抑制 ER 应激诱导的细胞凋亡显著增强了 HSCs 的再生能力。在机制上，CHOP 上调 EVA1A 蛋白的表达，从而通过 MCL1 促进 ER-线粒体连接，导致线粒体介导的细胞凋亡。这些发现揭示了 EVA1A 介导的细胞凋亡通过 EVA1A 介导的细胞凋亡参与 HSCs 的 ER 应激反应的途径，在 HSCs 的再生中发挥重要作用。
