Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4–CHOP–CHAC1 Signal Pathway in IPEC-J2 Cells,Journal of Agricultural and Food Chemistry

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Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4–CHOP–CHAC1 Signal Pathway in IPEC-J2 Cells
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2021-12-17 , DOI: 10.1021/acs.jafc.1c03361
Yanjun Cui ₁ , Xu Zhou ₁ , Leyi Chen ₁ , Zhining Tang ₁ , Fan Mo ₁ , Xiang Chen Li ₁ , Huiling Mao ₁ , Xiaoshi Wei ₁ , Chong Wang ₁ , Haifeng Wang ₂

Affiliation

The intestinal epithelium is susceptible to heat stress (HS), which leads to gut leakage and inflammation. However, the mechanisms underlying HS-induced intestine dysfunction have yet to be elucidated. We established an in vitro chronic heat exposure-induced intestinal injury of intestinal porcine epithelial cells (IPEC-J2) exposed to high temperatures (43 °C) for 12 h. The results revealed that HS increased reactive oxygen species (ROS) generation and decreased superoxide dismutase 2 (SOD2) expression, leading to oxidative stress. Western blotting analysis demonstrated that HS induced apoptosis as evidenced by increased cytochrome c (Cyt c) release in the cytoplasm and caspase 3 activation. Transcriptome sequencing analysis revealed that HS activated the endoplasmic reticulum stress (ERS) response/unfolded protein response (UPR) but inhibited glutathione metabolism. Specifically, HS triggered the pro-apoptotic activating transcription factor 4 (ATF4)/CEBP-homologous protein (CHOP) branch of the UPR. Interestingly, glutathione-specific gamma-glutamylcyclotransferase1 (CHAC1) involved in glutathione degradation was upregulated due to heat exposure and was proved to be downstream of the ATF4–CHOP signal pathway. Knockdown of CHAC1 attenuated the HS-induced decrease in glutathione level and cell apoptosis. These studies suggest that crosstalk between ERS and oxidative stress in HS-induced apoptosis might be dependent on the ATF4–CHOP–CHAC1 signal pathway in IPEC-J2 cells.

中文翻译：

热暴露诱导的细胞凋亡中内质网应激和氧化应激之间的串扰取决于 IPEC-J2 细胞中的 ATF4-CHOP-CHAC1 信号通路

肠上皮易受热应激 (HS) 影响，从而导致肠道渗漏和炎症。然而，HS 诱导肠道功能障碍的机制尚未阐明。我们建立了暴露于高温（43°C）12小时的猪肠上皮细胞（IPEC-J2）的体外慢性热暴露诱导的肠道损伤。结果表明，HS 增加了活性氧 (ROS) 的产生并降低了超氧化物歧化酶 2 (SOD2) 的表达，导致氧化应激。蛋白质印迹分析表明 HS 诱导细胞凋亡，如细胞色素c (Cyt c) 在细胞质中释放和 caspase 3 激活。转录组测序分析显示，HS 激活了内质网应激 (ERS) 反应/未折叠蛋白反应 (UPR)，但抑制了谷胱甘肽代谢。具体来说，HS 触发了 UPR 的促凋亡激活转录因子 4（ATF4）/CEBP 同源蛋白（CHOP）分支。有趣的是，参与谷胱甘肽降解的谷胱甘肽特异性γ-谷氨酰环转移酶1（CHAC1）由于热暴露而上调，并被证明是ATF4-CHOP信号通路的下游。CHAC1 的敲低减弱了 HS 诱导的谷胱甘肽水平和细胞凋亡的降低。这些研究表明，在 HS 诱导的细胞凋亡中，ERS 与氧化应激之间的串扰可能取决于 IPEC-J2 细胞中的 ATF4-CHOP-CHAC1 信号通路。

更新日期：2021-12-29

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