RIPK3 in necroptosis and cancer

Abstract

Receptor-interacting protein kinase-3 is essential for the cell death pathway called necroptosis. Necroptosis is activated by the death receptor ligands and pattern recognition receptors of the innate immune system, leading to significant consequences in inflammation and in diseases, particularly cancer. Necroptosis is highly proinflammatory compared with other modes of cell death because cell membrane integrity is lost, resulting in releases of cytokines and damage-associated molecular patterns that potentiate inflammation and activate the immune system. We discuss various ways that necroptosis is triggered along with its potential role in cancer and therapy.

Keywords: Cancer cell death; Damage-associated molecular patterns; MLKL; Necroptosis; Receptor-interacting protein kinase-3.

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), TRAIL receptor, Toll-like receptors (TLR3/4), CD95, and FAS. In the first 3 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 Z-DNA-binding protein-1 (ZBP1)/DAI, 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. Protein phosphatase 1B suppresses necroptosis by dephosphorylating RIPK3.

Fig. 2

Release of damage-associated molecular patterns through necroptosis activation induces robust antitumoral immunity. Induction of cell death through necroptosis promotes the release of damage-associated molecular patterns, activating immune responses, and modulating the tumor microenvironment.