Enterovirus 71 (EV71) infection causes hand, foot, and mouth disease (HFMD), and even fatal neurological complications. However, the mechanisms underlying EV71 neurological pathogeneses are largely unknown. This study reveals a distinct mechanism by which EV71 induces apoptosis and autophagy in neural cells. EV71 non-structure protein 3D (also known as RNA-dependent RNA polymerase, RdRp) interacts with the peroxisomal protein acyl-CoA oxidase 1 (ACOX1), and contributes to ACOX1 downregulation. Further studies demonstrate that EV71 reduces peroxisome numbers. Additionally, knockdown of ACOX1 or peroxin 19 (PEX19) induces apoptosis and autophagy in neural cells including human neuroblastoma (SK-N-SH) cells and human astrocytoma (U251) cells, and EV71 infection induces neural cell death through attenuating ACOX1 production. Moreover, EV71 infection and ACOX1 knockdown facilitate reactive oxygen species (ROS) production and attenuate the cytoprotective protein deglycase (DJ-1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme oxygenase 1 (HO-1) pathway (DJ-1/NRF2/HO-1), which collectively result in ROS accumulation in neural cells. In conclusion, EV71 downregulates ACOX1 protein expression, reduces peroxisome numbers, enhances ROS generation, and attenuates the DJ-1/NRF2/HO-1 pathway, thereby inducing apoptosis and autophagy in neural cells. These findings provide new insights into the mechanism underlying EV71-induced neural pathogenesis, and suggest potential treatments for EV71-associated diseases.

中文翻译：

---

肠病毒71通过促进ACOX1下调和ROS生成来诱导神经细胞凋亡和自噬。

肠病毒71（EV71）感染会导致手足口病（HFMD），甚至导致致命的神经系统并发症。但是，EV71神经病原学的潜在机制很大程度上未知。这项研究揭示了EV71诱导神经细胞凋亡和自噬的独特机制。EV71非结构蛋白3D（也称为RNA依赖性RNA聚合酶，RdRp）与过氧化物酶体蛋白酰基辅酶A氧化酶1（ACOX1）相互作用，并导致ACOX1下调。进一步的研究表明，EV71减少了过氧化物酶的数量。此外，敲低ACOX1或过氧化物酶19（PEX19）会诱导神经细胞的凋亡和自噬，包括人类神经母细胞瘤（SK-N-SH）细胞和人类星形细胞瘤（U251）细胞，而EV71感染会通过减弱ACOX1的产生诱导神经细胞死亡。此外，EV71感染和ACOX1敲低促进了活性氧（ROS）的产生，并减弱了细胞保护性蛋白质脱糖酶（DJ-1）/核因子红系2相关因子2（NRF2）/血红素加氧酶1（HO-1）途径（DJ-1） / NRF2 / HO-1），共同导致ROS在神经细胞中积聚。总之，EV71下调ACOX1蛋白表达，减少过氧化物酶体数目，增强ROS生成，并减弱DJ-1 / NRF2 / HO-1途径，从而诱导神经细胞凋亡和自噬。这些发现为EV71诱导的神经发病机理提供了新的见解，并提出了与EV71相关疾病的潜在治疗方法。