RIPK1 and RIPK3: critical regulators of inflammation and cell death

• RIPK1 has a scaffold function that inhibits apoptosis and necroptosis.
• The kinase activity of RIPK1 promotes apoptosis and necroptosis.
• The kinase activity of RIPK3 promotes necroptosis.
• Mutation of the kinase DFG motif in RIPK3 promotes apoptosis.

RIPK1 and RIPK3 (receptor-interacting serine/threonine protein kinases 1/3) interact by virtue of their RIP homotypic interaction motifs to mediate a form of cell death called necroptosis, although mice lacking these kinases have very different phenotypes. RIPK1-deficient mice die soon after birth, whereas RIPK3-deficient mice are healthy. Necroptosis involves cell rupture and is triggered by tumor necrosis factor (TNF), Toll-like receptors (TLRs), or the T cell receptor (TCR) when pro-apoptotic caspase-8 is inhibited. Various mouse models of disease are ameliorated by RIPK3 deficiency, suggesting that necroptosis contributes to pathology. Genetic rescue experiments now reveal why RIPK3-deficient are viable but RIPK1-deficient mice are not. These and other experiments indicate unexpected complexity in the regulation of both apoptosis and necroptosis by RIPK1 and RIPK3.