RIPK1 Kinase-Dependent Death: A Symphony of Phosphorylation Events

The serine/threonine kinase RIPK1 has emerged as a crucial component of the inflammatory response activated downstream of several immune receptors, where it paradoxically functions as a scaffold to protect the cell from death or instead as an active kinase to promote the killing of the cell. While RIPK1 kinase-dependent cell death has revealed its physiological importance in the context of microbial infection, aberrant activation of RIPK1 is also demonstrated to promote cell death-driven inflammatory pathologies, highlighting the importance of fundamentally understanding proper RIPK1 regulation. Recent advances in the field demonstrated the crucial role of phosphorylation in the fine-tuning of RIPK1 activation and, additionally, question the exact mechanism by which RIPK1 enzymatic activity transmits the death signal. RIPK1 kinase-dependent cell death drives inflammatory diseases in mice, and small molecule RIPK1 inhibitors are now in clinical trials to treat human patients with inflammatory pathologies.RIPK1 kinase activity is positively and negatively regulated by phosphorylation.TAK1, MK2, IKKα/β, TBK1/IKKε, NIK, and RIPK1 itself are reported to directly phosphorylate RIPK1.Phosphorylation of RIPK1 on serine 25 by IKKα/β serves as a physiological brake to repress RIPK1 enzymatic activity.No substrates of RIPK1, apart from itself, have been reported so far.