Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis
Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis
复制标题
DOI：
10.3164/jcbn.20-90
复制
发表时间：
2021-03-01
影响因子：
2.4
通讯作者：
Andoh, Akira
中科院分区：
文献类型：
--
作者：
Nishino, Kyohei;Nishida, Atsushi;Andoh, Akira
自噬相关基因已被确定为炎症性肠病的易感基因座。我们研究了核心自噬因子AtgS在葡聚糖硫酸钠（DSS）诱导的结肠炎发展中的作用。肠上皮细胞（IEC）特异性AtgS基因缺陷小鼠（Atg 5（Delta IEC）小鼠）通过Atg 5-floxed小鼠（Atg 5（fl/fl））与表达由绒毛蛋白启动子驱动的Cre重组酶的转基因小鼠杂交产生。在60天的时间段内，给予小鼠三个周期的1.5%DSS饮用水5天和普通水14天。在炎症性肠病患者的非炎症和炎症粘膜的上皮细胞中检测到自噬功能障碍，其特征在于自噬降解的底物p62蛋白的显著积累。与对照Atg 5（fl/fl）小鼠相比，DSS-结肠炎在Atg 5（Delta IEC）小鼠中加重。DSS处理的Atg 5（Delta IEC）小鼠IEC中肌醇需要跨膜激酶/核酸内切酶1 α（IRE 1 α）（内质网应激的传感器）和c-Jun N-末端激酶（IRE 1 α的下游靶点）的磷酸化显著增强。磷酸化IRE 1 α的积累通过用自噬抑制剂氯喹处理而增强。DSS处理的Atg 5（Delta IEC）小鼠中凋亡IEC更丰富。这些研究结果表明，AtgS通过降解过量的p-IRE 1 α来抑制内质网应激诱导的IEC细胞凋亡。
Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, AtgS, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific AtgS gene deficient mice (Atg5(Delta IEC) mice) were generated by cross of Atg5-floxed mice (Atg5(fl/fl)) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5(Delta IEC) mice compared to control Atg5(fl/fl) mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1 alpha (IRE1 alpha), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1 alpha, were significantly enhanced in IECs in DSS-treated Atg5(Delta IEC) mice. Accumulation of phosphorylated IRE1 alpha was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5(Delta IEC) mice. These findings suggest that AtgS suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1 alpha.