Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling

The kinase RIPK1 is an essential signaling node in various innate immune signaling pathways being most extensively studied in the TNFR1 signaling pathway. TNF signaling can result in different biological outcomes including gene activation and cell death induction in the form of apoptosis or necroptosis. RIPK1 is believed to be crucial for regulating the balance between these opposing outcomes. It is therefore not surprising that RIPK1 is highly regulated, most notably by phosphorylation, ubiquitination, and their respective reversals. In this review, we discuss the biological functions of RIPK1 within the context of TNFR1 signaling. Finally, we discuss recent advances in the knowledge on three ubiquitin E3 ligases that exert regulatory functions on RIPK1 signaling: cIAP1, cIAP2, and LUBAC.

TrendsRIPK1 plays a central role in regulating gene activation, apoptosis, and necroptosis.RIPK1 positively and negatively regulates RIPK3- and Caspase-8-mediated cell death.Ubiquitination of RIPK1 by LUBAC and cIAP1/2 prevents RIPK1-mediated death signaling.