RIP1 Oxidation Is Promoted By Mitochondrial ROS And Is Essential For Promoting TNF-induced Necroptosis

Necroptosis is a type of programmed cell death which has been found to be involved in many physiological and pathological processes,such as host defense against viruses,inflammatory reaction,damage of tissue,atherosclerosis,etc.Tumor necrosis factor(TNF)is a significant cytokine in vitro,which can trigger necroptosis.Previous studies showed that reactive oxygen species(ROS)can promote necroptosis in mouse fibroblast cell line L929 and enhance the formation of necrosome.Furthermore,both ROS scavenger,butylated hydroxyanisole(BHA)and the inhibitor of electron transport chain,Amytal can inhibit TNF-induced necroptosis.However,how ROS function is still unknown.We found that ROS is involoved in necroptosis in some cell lines of which aerobic respiration can be enhanced by TNF.Also,this kind of cell death could be inhibited by BHA and Amytal.Moreover,receptor-interacting protein 1(RIP1)plays an essential role in ROS-involved necroptosis.There are three cysteines in RIP which are oxidized in response to ROS.After that,RIP1 can form high molecular weight complex through disulfide bonds which is significant for necroptosis signal transduction.In this study,we demonstrated the mechanism of how ROS promote necrosis preliminarily which improved our knowledge about understanding the molecular mechanism of necroptosis.Most importantly,this study can provide some theoretical basis for the treatment of necroptosis-associated disease.