Mechanisms of TNF-independent RIPK3-mediated cell death

Abstract

Apoptosis and necroptosis regulate many aspects of organismal biology and are involved in various human diseases. TNF is well known to induce both of these forms of cell death and the underlying mechanisms have been elaborately described. However, cells can also engage apoptosis and necroptosis through TNF-independent mechanisms, involving, for example, activation of the pattern recognition receptors Toll-like receptor (TLR)-3 and -4, or zDNA-binding protein 1 (ZBP1). In this context, cell death signaling depends on the presence of receptor-interacting serine/threonine protein kinase 3 (RIPK3). Whereas RIPK3 is required for TNF-induced necroptosis, it mediates both apoptosis and necroptosis upon TLR3/4 and ZBP1 engagement. Here, we review the intricate mechanisms by which TNF-independent cell death is regulated by RIPK3.

Keywords: RIPK3; apoptosis; cell death; immunology; inflammation; necroptosis.

Figure 1.. Pathways leading to extrinsic apoptosis and necroptosis.

Upon engagement of death receptors such as TRAIL-R, CD95, and TNFR1, FADD recruits caspase-8 and cFLIP to regulate apoptosis. Caspase-8 homodimerization mediates apoptosis, whereas caspase-8 — cFLIP heterodimerization impairs apoptosis. TNFR1 engagement also results in RIPK1-mediated cell death. RIPK1 can engage with FADD to regulate apoptosis and RIPK3 to mediate necroptosis. RIPK1 — RIPK3 activation is controlled by the FADD — caspase-8 — cFLIP complex. Activation of TRIF-dependent TLRs or ZBP1 mediates cell death through association with RIPK3 and RIPK1. RIPK3 recruits MLKL to mediate necroptosis, which is controlled by the RIPK1 — FADD — caspase-8 — cFLIP complex. RIPK3 can mediate apoptotic signals to FADD — caspase-8. Type I and type II interferons induce the gene expression of ZBP1. Black arrows indicate death receptor-mediated pathways. Blue arrows indicate non-death receptor-mediated pathways.

Figure 2.. Regulation of non-TNF directed RIPK3-mediated death signals.

Activated RIPK3 is able to induce both apoptosis and necroptosis. Disruption of the RIPK3 RHIM impairs both apoptosis and necroptosis. RIPK3 kinase inactivity or failure to phosphorylate RIPK3 T231/S232 impairs necroptosis but promotes apoptosis, a process that is furthermore regulated by cIAPs and TAK1. RIPK1, FADD, or caspase-8 deficiency, blocking the catalytic activity of caspase-8, or disruption of the RIPK1 RHIM promotes necroptosis and impairs apoptosis, although apoptosis can ensue under certain conditions in absence of RIPK1. Blocking the proteosome primarily promotes necroptosis, although apoptosis can also ensue.