cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation

Area of Science:

• Immunology
• Molecular Biology
• Cell Death Pathways

Background:

• Cellular inhibitor of apoptosis proteins (cIAPs) are E3 ubiquitin ligases crucial for regulating TNF signaling.
• cIAPs ubiquitylate receptor-interacting protein kinase 1 (RIPK1), a key mediator of TNF-induced cell death.
• Dysregulation of TNF signaling is implicated in various inflammatory diseases.

Purpose of the Study:

• To investigate the role of cIAPs in TNF signaling and cell death.
• To establish a novel mouse model for studying cIAP function.
• To elucidate the interplay between cIAPs, RIPK1, RIPK3, and TNFR1 in vivo.

Main Methods:

• Generation of mice with enzymatically inactive cIAP1/2 variants (cIAP1/2^MutR).
• Creation of compound mutant mice, including Ripk1^D138N and Tnfr1 knockout.
• Phenotypic analysis of mutant mice, focusing on embryonic development, survival, and systemic inflammation.

Main Results:

• cIap1/2^MutR/MutR mice exhibited embryonic lethality due to RIPK1-mediated apoptosis.
• Kinase-inactive RIPK1 partially rescued development, but Ripk1^D138N/D138N /cIap1/2^MutR/MutR mice showed postweaning mortality with systemic inflammation.
• TNFR1 deficiency prevented inflammation and mortality, indicating cIAPs regulate TNFR1-mediated toxicity independently of RIPK1 and RIPK3.

Conclusions:

• cIAPs play a critical role in preventing TNF-induced toxicity through mechanisms partially independent of RIPK1 kinase activity.
• TNFR1 signaling is a key pathway through which cIAPs exert their protective effects against systemic inflammation.
• The developed mouse model provides a valuable tool for studying TNF signaling and evaluating therapies targeting TNF, cIAPs, and RIPK1.