Gut stem cell necroptosis by genome instability triggers bowel inflammation
Gut stem cell necroptosis by genome instability triggers bowel inflammation
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基因组不稳定引起的肠道干细胞坏死性凋亡引发肠道炎症
DOI：
10.1038/s41586-020-2127-x
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发表时间：
2020-03-25
期刊：
影响因子：
64.8
通讯作者：
Mo, Wei
中科院分区：
文献类型：
--
作者：
Wang, Ruicong;Li, Hongda;Mo, Wei
炎症性肠病（IBD）的病因是遗传和环境之间的多因素相互作用。在这里，我们报告说，缺乏SETDB 1，组蛋白甲基转移酶，介导的三甲基化组蛋白H3在赖氨酸9，参与IBD的发病机制。我们发现IBD患者的SETDB 1水平降低，并且肠道干细胞中SETDB 1减少的小鼠发生自发性末端回肠炎和结肠炎。SETDB 1保护基因组稳定性，并且肠道干细胞中SETDB 1的丢失释放了内源性逆转录病毒（具有长重复序列的逆转录病毒样元件，在人类中，其占基因组的约8%）的抑制。由内源性逆转录病毒引起的过度病毒模仿触发了Z-DNA结合蛋白1（ZBP 1）依赖性坏死性凋亡，这不可逆地破坏了上皮屏障的稳态并促进了肠道炎症。基因组不稳定性，反应性内源性逆转录病毒，ZBP 1的上调和坏死性凋亡均见于IBD患者。RIP 3的药物抑制在SETDB 1缺陷小鼠中显示出疗效，这表明靶向肠干细胞坏死性凋亡可能代表治疗严重IBD的方法。
The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between heredity and environment,. Here we report that deficiency in SETDB1, a histone methyltransferase that mediates the trimethylation of histone H3 at lysine 9, participates in the pathogenesis of IBD. We found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability, and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses (retrovirus-like elements with long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.