Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells
Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells
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DOI：
10.1038/s41556-019-0285-6
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发表时间：
2019-03-01
影响因子：
21.3
通讯作者：
Li, Qing
中科院分区：
文献类型：
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作者：
Liu, Lu;Zhao, Meiling;Li, Qing
在它们的一生中，长期造血干细胞（HSC）暴露于它们必须忍受的各种应激条件。许多应激，如感染/炎症、活性氧、营养剥夺和缺氧，激活未折叠蛋白反应信号传导，其诱导适应性变化以解决应激或凋亡以清除受损细胞。未折叠蛋白反应信号传导是否在HSC调节中发挥任何作用仍有待确定。在这里，我们报告说，适应性信号的未折叠的蛋白质反应，IRE 1 α-XBP 1，保护肝星状细胞从内质网应激诱导凋亡。IRE 1 α敲除导致HSC重建减少。此外，我们发现致癌N-Ras（G12 D）通过MEK-GSK 3 β激活IRE 1 α-XBP 1，以促进内质网应激下HSC的存活。抑制IRE 1 α-XBP 1消除了内质网应激下N-Ras（G12 D）介导的存活，并降低了移植受体中Nras（G12 D）HSC的竞争优势。我们的研究阐明了适应性内质网应激反应如何有利于维持HSC的自我更新和促进白血病前克隆优势。
Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established. Here, we report that the adaptive signalling of the unfolded protein response, IRE1 alpha-XBP1, protects HSCs from endoplasmic reticulum stress-induced apoptosis. IRE1 alpha knockout leads to reduced reconstitution of HSCs. Furthermore, we show that oncogenic N-Ras(G12D) activates IRE1 alpha-XBP1, through MEK-GSK3 beta, to promote HSC survival under endoplasmic reticulum stress. Inhibiting IRE1 alpha-XBP1 abolished N-Ras(G12D)-mediated survival under endoplasmic reticulum stress and diminished the competitive advantage of Nras(G12D) HSCs in transplant recipients. Our studies illuminate how the adaptive endoplasmic reticulum stress response is advantageous in sustaining self-renewal of HSCs and promoting pre-leukaemic clonal dominance.