Division of Emergency Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
FASEB J. 2019 Sep;33(9):10165-10176. doi: 10.1096/fj.201900376RRR. Epub 2019 Jun 19.
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 β-arrestin1 (βarr1) in radiation-induced intestinal injury. Intestinal βarr1 was highly expressed in radiation enteritis and in a radiation model. βarr1 knockout (KO) or knockdown mice exhibited increased proliferation in intestinal Lgr5+ stem cell, crypt reproduction, and survival following radiation. Unexpectedly, the beneficial effects of βarr1 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-2α (eIF2α) pathway was inhibited, and this result was further supported . Furthermore, we found that βarr1 knockdown with small interfering RNA significantly enhanced intestinal Lgr5 stem cell proliferation after radiation directly targeting PERK. βarr1 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. β-Arrestin1-mediated decrease in endoplasmic reticulum stress impairs intestinal stem cell proliferation following radiation.
胃肠道毒性限制了腹部和盆腔放射治疗的临床应用，目前尚无有效治疗方法。由于辐射，肠道富含亮氨酸重复序列的 G 蛋白偶联受体 5（Lgr5）阳性干细胞耗竭和增殖能力丧失可能是辐射后肠损伤的主要因素。在这里，我们报告了β-arrestin1（βarr1）在辐射诱导的肠损伤中的关键作用。βarr1 在放射性肠炎和放射模型中高度表达。βarr1 敲除（KO）或敲低小鼠在辐射后表现出肠道 Lgr5+干细胞增殖增加、隐窝繁殖和存活增加。出乎意料的是，当抑制内质网应激相关蛋白激酶 RNA 样内质网激酶（PERK）/真核起始因子 2α（eIF2α）通路时，βarr1 缺乏对辐射后肠干细胞的有益作用受到损害，这一结果进一步得到支持。此外，我们发现用小干扰 RNA 敲低 βarr1 可显著增强辐射后肠 Lgr5 干细胞增殖，直接靶向 PERK。βarr1 为减轻辐射诱导的肠道损伤提供了一个有前途的靶点。
