The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis

Programmed necrosis in response to TNF requires the activity of two serine-threonine kinases. The history of tumor necrosis factor (TNF) incorporates many facets of cell biology, immunology, and pathophysiology. The historical name “TNF” emphasizes its capacity to induce hemorrhagic necrosis of tumors, which refers to a histological feature. However, TNF is now known as a multifunctional cytokine that mediates cell death and inflammation following infection or tissue injury. The ability of TNF to cause cachexia and wasting during chronic neoplastic and infectious diseases suggests a link with metabolism. Here, we report on the different signaling pathways that determine whether the cellular outcome of TNF signaling is gene induction and survival, apoptosis, or programmed necrosis. Programmed necrosis is also called necroptosis, a regulated form of necrotic cell death that occurs in the absence of caspase activation and that can be blocked by inhibiting RIP1 (receptor-interacting protein 1). The kinases RIP1 and RIP3, which are regulated by caspases and ubiquitination, are key initiators of programmed necrosis. However, it remains unclear precisely how RIP1 and RIP3 instigate the execution pathways of programmed necrosis, which involve several cellular processes, such as increased bioenergetics, increased reactive oxygen species production, calcium mobilization, activation of phospholipases and acid sphingomyelinases, and destabilization of lysosomes. Because necrosis occurs in different conditions—such as myocardial infarction, stroke, pancreatitis, and viral infections—kinase inhibitors of RIP1 and RIP3 could be used or developed to prevent pathological cell death. This review highlights TNF-induced mechanisms of programmed necrosis mediated by the kinases RIP1 and RIP3, and contains three figures and 102 references. Tumor necrosis factor (TNF) is a pleiotropic molecule with a crucial role in cellular stress and inflammation during infection, tissue damage, and cancer. TNF signaling can lead to three distinct outcomes, each of which is initiated by different signaling complexes: the gene induction or survival mode, the apoptosis mode, and the necrosis mode. The kinases receptor-interacting protein 1 (RIP1) and RIP3 are key signaling molecules in necrosis and are regulated by caspases and ubiquitination. Moreover, TNF stimulation induces the formation of a necrosome in which RIP3 is activated and interacts with enzymes that control glycolytic flux and glutaminolysis. The necrosome induces mitochondrial complex I–mediated production of reactive oxygen species (ROS) and cytotoxicity, which suggest a functional link between increased bioenergetics and necrosis. In addition, other effector mechanisms also contribute to TNF-induced necrosis, such as recruitment of NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) oxidases and subsequent ROS production at the membrane-associated TNF receptor complex I; calcium mobilization; activation of phospholipase A2, lipoxygenases, and acid sphingomyelinases; and lysosomal destabilization. However, the link between RIP1 and RIP3 and these subcellular events remains to be established. The regulation of RIP1 and RIP3 and their downstream signaling cascades opens new therapeutic avenues for treatment of pathologies associated with cell loss, such as ischemia-reperfusion damage and neurodegeneration, and ways to stimulate alternative immunogenic cell death pathways in cancer.