Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia-reperfusion injury
Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia-reperfusion injury
复制标题
FBXW7 抑制 HSF1 泛素化可保护肠道免受缺血再灌注损伤。
DOI：
10.1007/s10495-018-1484-5
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发表时间：
2018-12-01
期刊：
影响因子：
7.2
通讯作者：
Tian, Xiaofeng
中科院分区：
文献类型：
--
作者：
Tan, Wenzhi;Zhao, Huanyu;Tian, Xiaofeng
肠上皮细胞凋亡是肠缺血再灌注损伤的重要因素。热休克因子1(HSF1)是一种经典的应激反应因子，在应激条件下直接调节热休克蛋白(HSPs)的转录。虽然热休克蛋白参与保护肠道免受I/R损伤，但HSF1在I/R中的调控机制尚不清楚。在这项研究中，我们发现泛素连接酶FBXW7针对HSF1在肠I/R中的泛素化和降解。在本研究中，我们发现FBXW7在I/R时在肠粘膜的转录水平上上调。在缺氧/复氧(H/R)的Caco-2和IEC-6细胞中，高水平的FBXW7导致HSF1泛素化和降解过度。Fbxw7基因敲除可抑制HSF1泛素化和下调，促进HSPB1和HSP70的表达。此外，FBXW7基因缺失减轻了肠上皮细胞的凋亡，表现为caspase-3和caspase-9活性降低。结果表明，抑制FBXW7对肠道I/R具有保护作用，至少部分是通过HSF1/HSP途径实现的。提示FBXW7可能是抑制肠I/R时肠粘膜细胞凋亡的潜在治疗靶点。
Epithelial apoptosis is an important factor in intestinal ischemia-reperfusion (I/R) injury. Heat shock factor 1 (HSF1) is a classical stress response factor that directly regulates the transcription of heat shock proteins (HSPs) under stress conditions. Although HSPs are involved in protecting the intestine against I/R, the mechanism whereby HSF1 is regulated in I/R is poorly understood. Here, we show that the ubiquitin ligase FBXW7 targets HSF1 for ubiquitination and degradation in intestinal I/R. In this study, we found that FBXW7 expression was upregulated at the transcriptional level in intestinal mucosae subjected to I/R. In Caco-2 and IEC-6 cells subjected to hypoxia/reoxygenation (H/R), a high FBXW7 level led to excessive HSF1 ubiquitination and degradation. FBXW7 knockdown attenuated HSF1 ubiquitination and downregulation and accelerated HSPB1 and HSP70 expression. In addition, FBXW7 deletion alleviated the apoptosis of intestinal epithelial cells, as evidenced by decreased activation of caspase-3 and caspase-9. The results suggest that FBXW7 suppression protects against intestinal I/R, at least partly through the HSF1/HSP pathway. These findings indicate that FBXW7 may be a potential therapeutic target for inhibiting intestinal mucosa apoptosis during intestinal I/R.