Enterovirus 71 Induces Neural Cell Apoptosis And Autophagy Through Promoting ACOX1 Degradation And ROS Accumulation

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)through its palm domain,and contributes to ACOX1 degradation.Further studies demonstrate that EV71 attenuates peroxisome biogenesis.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.Finally,we reveal that ACOX1 knockdown promotes EV71 replication through facilitating ROS generation in neural cells,and show that antioxidants N-acetylcysteine(NAC)and ?-lipoic acid(LA)scavenge EV71-induced ROS generation,inhibit EV71 replication,and protect neural cells from death.In conclusion,EV71 facilitates proteasome-mediated ACOX1 degradation,reduces peroxisome biogenesis,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.