Roles of RIPK3 in necroptosis, cell signaling, and disease

Abstract

Receptor-interacting protein kinase-3 (RIPK3, or RIP3) is an essential protein in the “programmed” and “regulated” cell death pathway called necroptosis. Necroptosis is activated by the death receptor ligands and pattern recognition receptors of the innate immune system, and the findings of many reports have suggested that necroptosis is highly significant in health and human disease. This significance is largely because necroptosis is distinguished from other modes of cell death, especially apoptosis, in that it is highly proinflammatory given that cell membrane integrity is lost, triggering the activation of the immune system and inflammation. Here, we discuss the roles of RIPK3 in cell signaling, along with its role in necroptosis and various pathways that trigger RIPK3 activation and cell death. Lastly, we consider pathological situations in which RIPK3/necroptosis may play a role.

Cell death: Multiple roles for enzyme

Further research into the various roles of an enzyme involved in necroptosis, a form of programmed cell death, could present novel therapeutics for multiple diseases. Necroptosis involves the rupture of cellular membranes in response to stress, for example when the body is under attack from pathogens. The contents of the cell spill out, triggering a proinflammatory immune response. You-Sun Kim at Ajou University in Suwon, South Korea, and Michael Morgan at Northeastern State University in Tahlequah, USA, reviewed the activity of receptor-interacting protein kinase 3 (RIPK3) in cell signaling and necroptosis. In initiating necroptosis, RIPK3 forms a complex with another enzyme, which then activates a protein involved in regulating membrane permeability. Disruption of necroptosis is implicated in inflammatory and neurodegenerative diseases, cancers, and conditions involving tissue damage such as heart disease.