Role of RIP3 in Necrotic Cell Death

Abstract

Gradually, it has been realized that some necrotic cell deaths are tightly controlled. Accumulating evidence has demonstrated that similar to apoptosis, cellular necrosis also plays an essential role in developmental and pathophysiological processes. Receptor-interacting protein 3 (RIP3)-dependent necrosis (also termed necroptosis) is a programmed necrosis that occurs when cells are exposed to a death stimulus such as tumor necrosis factor (TNF). Necroptosis also occurs in development and some disease conditions when caspase-8 is inhibited or RIP3 is upregulated. TNF-induced necroptosis is the most studied necrosis pathway. Based on its model system, RIP3 acts in a complex with RIP1 to mediate a necrosis signal; RIP1 alone, however, initiates apoptosis. This RIP3/RIP1 complex is termed the necrosome. RIP3 appears to be a switch molecule that converts apoptosis to necroptosis. On the other hand, caspase-8 is capable of cleaving RIP1 and RIP3 in the necrosome and therefore is a negative regulator of necroptosis. Going from signaling to necrosis execution requires mixed lineage kinase domain-like (MLKL), which most likely acts as a scaffold protein. Whether it has kinase activity, however, is still in debate. A number of events downstream of the necrosome have also been reported. Mitochondrial reactive oxygen species (ROS) production has been implicated in TNF-induced necroptosis but might be cell type dependent. RIP3 can directly interact with and enhance the activity of the energy metabolism-related enzymes, glycogen phosphorylase (PYGL), glutamate-ammonia ligase (GLUL; also called glutamine synthetase), and mitochondrial matrix-localized glutamate dehydrogenase 1 (GLUD1) and thus contributes to the ROS production. Mitochondrial phosphoglycerate mutase 5 (PGAM5) was recently implicated to be a direct substrate of RIP3. PGAM5 can dephosphorylate GTPase dynamin-related protein-1 (Drp1) and thus induces mitochondrial fission. Further understanding of the mechanisms of RIP3-mediated necroptosis is not only an interest in the fields of cell biology and immunology but also a need for our fight against necrosis-related diseases.