Identification And Mechanism Of RIP3 As A Molecular Switch Between Apoptosis And Necrosis

Cell death has been subdivided into the morphologically distinct processes ofapoptosis and necrosis.Apoptosis is the process of programmed cell death,whilenecrosis is a form of traumatic cell death that occurs under a variety of physologicaland pathological conditions.Despite of the belief that necrosis might also be mediatedby some programs,it is still a challenge to characterize the precise mechanismsunderlying programmed necrosis and the molecular switches between apoptosis andnecrosis.Tumor necrosis factor (TNF)can trigger different types of cell death in twoNIH-3T3 cell lines which are derived from the same cell origin.By using theapproaches of genetics and molecular biology,we have identified receptor-interactingprotein 3 (RIP3)as the main cause of the different cell death,and found that RIP3 is amolecular switch between TNF-induced apoptosis and necrosis in NIH-3T3 cells.RIP3 does not affect RIP1-mediated apoptosis but is required for RIP1-mediatednecrosis and that is further enhanced by pan caspase inhibitor zVAD.RIP3 is alsoresponsible for necrosis in other cells.We have further revealed that RIP3 can regulate cellular energy metabolismwhich affects necrotic cell death.RIP3 interacts with and enhances key enzymes ofmetabolic pathway PYGL (glycogen phosphorylase),GLUL (glutamate-ammonialigase),and GLUD1 (glutamate dehydrogenase 1).These increase cellular energymetabolism level and reactive oxygen species (ROS)from mitochondrial respirationchain that partially accounts for RIP3's ability to promote necrosis.In this study,we have found RIP3 functions as the molecular switch betweenapoptosis and necrosis.We have also revealed that RIP3 mediates necrosis at leastpartly through increasing energy metabolism-associated ROS production.Ourresearch has elucidated a detailed molecular mechanism of necrosis and the cause of necrosis-related diseases.Since deletion of RIP3 can improve the condition of acutepancreatitis in a mouse model,RIP3 could become a potential drug target for thesediseases.