Selenium utilization by GPX4 Is required to prevent hydroperoxide-induced ferroptosis. Caspase-8 acts in a non-enzymatic role as a SCAFFOLD for assembly of a pro-inflammatory “FADDosome” complex upon TRAIL Stimulation. Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression. Cyclophilin A release as a biomarker of necrotic cell death. Cyclophilin A: a key player for human disease. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Activation of necroptosis in multiple sclerosis. Identification of RIP1 kinase as a specific cellular target of necrostatins. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls.
Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients’ peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development 2, 3. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains.
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