Linear Ubiquitination of RIPK1 on Lys612 Regulates Systemic Inflammation via Preventing Cell Death

Area of Science:

• Immunology
• Molecular Biology
• Cell Death Research

Background:

• Receptor-interacting protein kinase-1 (RIPK1) regulates TNF-α-induced cell death pathways.
• Posttranslational modifications, like linear ubiquitination, control RIPK1 function.
• The precise role of RIPK1 linear ubiquitination in TNF-α signaling is not fully understood.

Purpose of the Study:

• To elucidate the physiological function and molecular mechanism of RIPK1 linear ubiquitination in TNF-α signaling.
• To investigate the impact of RIPK1 linear ubiquitination on systemic inflammation and hematopoiesis.

Main Methods:

• Identification of the major linear ubiquitination site on human and murine RIPK1 (Lys627/Lys612).
• Generation and analysis of Ripk1 mutant mice.
• Genetic deletion of TNF receptor 1, RIPK3, and Caspase-8 in Ripk1 mutant mice.

Main Results:

• Mutation of RIPK1 at Lys612 enhances TNF-α-induced apoptosis and necroptosis without affecting NF-κB activation.
• Ripk1 mutant mice exhibit spontaneous systemic inflammation and hematopoietic disorders.
• Systemic inflammation and hematopoietic issues in Ripk1 mice are rescued by deleting TNF receptor 1 or RIPK3 and Caspase-8.

Conclusions:

• Linear ubiquitination of RIPK1 on Lys612 is crucial for restricting TNF-α-induced cell death.
• This modification acts as a critical brake on cell death pathways, preventing the development of systemic inflammation and associated hematopoietic disorders.