RIP3: a molecular switch for necrosis and inflammation

Abstract

The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases.

Keywords: FADD; MLKL; PGAM5; RIP1; caspase 8; inflammation.

Figure 1.

Domain organization of human RIP family proteins. The phospho-acceptor sites are highlighted with the letter P. The crucial lysine residues in the ATP-binding pocket are shown (K45 in RIP1, K47 in RIP2, K50 in RIP3, and K51 in RIP4). M92 is the “gatekeeper residue” in RIP1 that is important for kinase activity (Lu et al. 2011).

Figure 2.

Overview of RIP3-dependent necrosis and inflammation. Ligation of TNF to TNF-R1 leads to the formation of complex I, where RIP1 is ubiquitinated by cIAP1/2 and LUBAC. Deubiquitination of RIP1 by CYLD converts the signal from cell survival to cell death by facilitating the formation of complex II. Fas ligand and TRAIL also induce complex II formation. Active caspase-8 in this complex induces apoptosis and inhibits necrosis by cleaving RIP1, RIP3, and CYLD. When caspase-8 is inhibited, the amyloid RIP1/RIP3 necrosome is formed. Necrosome formation causes necrosis through the mitochondrial pathway mediated by MLKL, recruitment of PGAM5_L and PGAM5s, and activation of Drp1. PGAM5 and Drp1 also mediate necrosis induced by ROS and calcium ionophore. TLR3 and TLR4 activation by pathogen-associated molecular patterns (PAMPs) such as dsRNA and LPS lead to RIP3 binding to TRIF and necrosis. For the T-cell receptor (TCR), the mechanism that activates RIP3-dependent necrosis is still unknown. Membrane rupture results in the release of DAMPs to an extracellular space where innate immune cells such as macrophages and DCs are located. These innate immune cells recognize DAMPs during infection or tissue damage to elicit an inflammatory cytokine response. Besides necrosis, RIP3 can also drive IL-1β production in caspase-8-deficient DCs or when IAP proteins are eliminated by SMs. (APC) Antigen-presenting cells; (MHC) major histocompatibility complex.