Zhao Ye, Zhu Xiaoxiao, Lan Qingyuan, Wei Ziang, Shang Pan, Song Lei, Hu Shijie, Chen Lei, Gan Mailin, Niu Lili, Wang Yan, Shen Linyuan, Zhu Li
State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
Int J Biol Macromol. 2024 Dec;283(Pt 1):137484. doi: 10.1016/j.ijbiomac.2024.137484. Epub 2024 Nov 9.
Rotavirus (RV) mainly infects mature intestinal epithelial cells and impairs intestinal absorption function, which leads to the death of infected cells and eventually fatal diarrhea. Ferroptosis is a novel regulatory cell death pattern, which can be caused by virus infection. 1α,25-hydroxyvitamin D (1,25D) has an anti-RV infection effect and can regulate ferroptosis. However, whether RV infection can induce ferroptosis, and whether 1,25D can inhibit RV infection by regulating ferroptosis has not yet been studied. Present study shows that RV infection or erastin treatment induces IPEC-J2 cell death, which results in mitochondrial shrinkage, decreased mitochondrial membrane potential (MMP) and glutathione (GSH) content, increased MMP, intracellular Fe, reactive oxygen species (ROS), and malondialdehyde (MDA) contents. Meanwhile, ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), and deferoxamine (DFO) treatment can effectively reverse the increase of intracellular Fe, ROS and MDA levels induced by RV infection. Moreover, RV infection increases activating transcription factor 3 (ATF3) mRNA and protein expressions, and inhibited SLC7A11 and glutathione peroxidase 4 (GPX4) expressions, which was partially alleviated by siATF3. 1,25D treatment significantly eliminates RV induced ferroptosis via ATF3-SLC7A11-GPX4 axis. Therefore, these results reveals that RV infection induces ferroptosis in IPEC-J2 cell and 1,25D alleviates RV induced ferroptosis by regulating the ATF3-SLC7A11-GPX4 axis.
轮状病毒（RV）主要感染成熟的肠道上皮细胞并损害肠道吸收功能，导致受感染细胞死亡并最终引发致命性腹泻。铁死亡是一种新型的调节性细胞死亡模式，可由病毒感染引起。1α,25-二羟基维生素D（1,25D）具有抗RV感染的作用，并且可以调节铁死亡。然而，RV感染是否能诱导铁死亡，以及1,25D是否能通过调节铁死亡来抑制RV感染尚未得到研究。目前的研究表明，RV感染或erastin处理可诱导IPEC-J2细胞死亡，导致线粒体萎缩、线粒体膜电位（MMP）和谷胱甘肽（GSH）含量降低，MMP、细胞内铁、活性氧（ROS）和丙二醛（MDA）含量增加。同时，铁抑素-1（Fer-1）、脂氧素-1（Lip-1）和去铁胺（DFO）处理可有效逆转RV感染诱导的细胞内铁、ROS和MDA水平的升高。此外，RV感染会增加激活转录因子3（ATF3）的mRNA和蛋白表达，并抑制溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的表达，而siATF3可部分缓解这种情况。1,25D处理可通过ATF3-SLC7A11-GPX4轴显著消除RV诱导的铁死亡。因此，这些结果表明，RV感染可诱导IPEC-J2细胞发生铁死亡，而1,25D通过调节ATF3-SLC7A11-GPX4轴减轻RV诱导的铁死亡。
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