β-Arrestin1-mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation
β-Arrestin1-mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation
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DOI：
10.1096/fj.201900376rrr
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Wu, Bin
中科院分区：
文献类型：
--
作者：
Liu, Zhihao;Jiang, Jie;Wu, Bin
胃肠道毒性限制了腹盆腔放疗的临床应用，目前尚无有效的治疗方法。肠道富含亮氨酸重复序列的GPCR 5（Lgr 5）阳性干细胞的耗竭和增殖能力的丧失可能是导致放射性肠道损伤的主要因素。在这里，我们报告的关键作用β-arrestin 1（β arr 1）在辐射诱导的肠道损伤。肠β arr 1在放射性肠炎和放射模型中高度表达。β arr 1敲除（KO）或敲减小鼠表现出肠Lgr 5+干细胞增殖、隐窝繁殖和辐射后存活率增加。出乎意料的是，当内质网应激相关蛋白激酶RNA样ER激酶（PERK）/真核起始因子-2 α（eIF 2 α）通路被抑制时，β arr 1缺陷对肠干细胞响应辐射的有益作用受到损害，并且该结果在体外得到进一步支持。此外，我们发现，小干扰RNA敲低β arr 1通过直接靶向PERK显著增强了辐射后肠道Lgr 5（+）干细胞的增殖。beta arr 1为减轻辐射引起的肠道损伤提供了一个有希望的靶点。刘志，姜杰，他，Q.，刘志，杨志，徐，J，黄志，吴，B。β-Arrestin 1介导的内质网应激减少损害辐射后肠干细胞增殖
Gastrointestinal toxicity limits the clinical application of abdominal and pelvic radiotherapy and currently has no effective treatment. Intestinal leucine-rich-repeat-containing GPCR 5 (Lgr5)-positive stem cell depletion and loss of proliferative ability due to radiation may be the primary factors causing intestinal injury following radiation. Here, we report the critical role of beta-arrestin1 (beta arr1) in radiation-induced intestinal injury. Intestinal beta arr1 was highly expressed in radiation enteritis and in a radiation model. beta arr1 knockout (KO) or knockdown mice exhibited increased proliferation in intestinal Lgr5+ stem cell, crypt reproduction, and survival following radiation. Unexpectedly, the beneficial effects of beta arr1 deficiency on intestinal stem cells in response to radiation were compromised when the endoplasmic reticulum stress-related protein kinase RNA-like ER kinase (PERK)/eukaryotic initiation factor-2 alpha (eIF2 alpha) pathway was inhibited, and this result was further supported in vitro. Furthermore, we found that beta arr1 knockdown with small interfering RNA significantly enhanced intestinal Lgr5(+) stem cell proliferation after radiation via directly targeting PERK. beta arr1 offers a promising target for mitigating radiation-induced intestinal injury.-Liu, Z., Jiang, J., He, Q., Liu, Z., Yang, Z., Xu, J., Huang, Z., Wu, B. beta-Arrestin1-mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation.