RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3

Area of Science:

• Cellular Biology
• Immunology
• Molecular Biology

Background:

• Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cell death and inflammation.
• Genetic ablation of RIPK1 leads to postnatal lethality, indicating its critical role in early life.
• RIPK1's precise function in various cell death pathways, including RIPK3-dependent and -independent signaling, requires further elucidation.

Purpose of the Study:

• To investigate the complex roles of RIPK1 in postnatal survival and its interactions with other cell death regulators.
• To clarify the involvement of RIPK1 in RIPK3-dependent and -independent signaling pathways.
• To understand how RIPK1 regulates TNFR-induced apoptosis and necroptosis.

Main Methods:

• Generation and analysis of genetically modified mouse models lacking RIPK1, RIPK3, caspase-8, FADD, and TNFR1.
• In vitro studies to assess RIPK1's function in caspase-8-dependent apoptosis.
• Investigation of cell death signaling pathways, including necroptosis, triggered by various stimuli like poly I:C and interferons.
• Analysis of the impact of disrupting Toll-like receptor (TLR) and type I interferon (IFNAR) signaling on lethality.

Main Results:

• Mice lacking RIPK1, RIPK3, and either caspase-8 or FADD survived to adulthood, unlike RIPK1-deficient mice alone.
• RIPK1 was found to limit caspase-8-dependent apoptosis in vitro.
• Animals lacking RIPK1, RIPK3, and TNFR1 survived to adulthood, suggesting RIPK1's role in TNFR1-mediated lethality.
• RIPK1 appears to inhibit RIPK3 activation postbirth, as RIPK3 deficiency exacerbates lethality in RIPK1-deficient mice.
• RIPK1 deficiency sensitized cells to necroptosis induced by poly I:C or interferons, despite RIPK1 being required for TNFR-induced necroptosis.
• Disrupting TRIF or IFNAR signaling delayed lethality in RIPK1 and TNFR1 double knockout mice.

Conclusions:

• RIPK1 plays a multifaceted role in regulating cell death and inflammation, essential for postnatal survival.
• The interplay between RIPK1, RIPK3, caspase-8, and FADD is critical for preventing lethality associated with RIPK1 deficiency.
• RIPK1 acts as a crucial checkpoint, inhibiting RIPK3-mediated lethality and modulating necroptosis signaling pathways.
• These findings provide significant insights into the complex regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.