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.

Fig. 1. Activation of RIPK3 by multiple stimuli.

RIPK3 can be activated via various receptors when bound by their respective ligands. These are TNF receptor 1 (TNF-R1), CD95, death receptors (DR4/5), Toll-like receptors (TLR3/4), and Z-DNA-binding protein-1 (ZBP1)/DAI. In the first three of these pathways (but not TLR3/4 or ZBP1), RIPK1 is required and binds to RIPK3 through its receptor-interacting protein homotypic interaction motif (RHIM). In the case of ZBP1, RIPK3 is recruited directly via the ZBP1 RHIM domain, while in the case of TLR3/4, RIPK3 is recruited indirectly via the RHIM domain of TRIF. Once activated, RIPK3 autophosphorylates and then phosphorylates and activates MLKL to induce a conformational change and translocation to the membrane, where membrane permeabilization follows. During this process, post-translational modifications positively and negatively regulate the necroptosis pathway. Two E3 ligases, Pellino-1 (PELI1) and carboxy terminus of HSC70-interacting protein (CHIP), may control the basal threshold of necroptosis. Another E3 ubiquitin ligase, TRIM21, is proposed to be a regulator of necroptotic cell death in response to TRAIL. PPM1B suppresses necroptosis by dephosphorylating RIPK3.

Fig. 2. Impact of RIPK3-mediated necroptosis in human diseases.

RIPK3-mediated necroptosis pathway dysregulation has been implicated in the pathophysiological processes of several human diseases, including various cancers and liver, cardiovascular, neurodegenerative, lung, pancreatic, intestinal, kidney, skin, and joint diseases.