CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis

Significance Necroptosis is a form of cell death implicated in many human diseases. A series of requirements has to be fulfilled before the cell makes the ultimate decision to die. One such essential event in necroptosis is the phosphorylation of RIPK3. It has previously been suggested that RIPK3 might phosphorylate itself. Here we discover that CK1 family kinases directly phosphorylate RIPK3. In cells without CK1 proteins, RIPK3 is not phosphorylated and the cells remain alive when exposed to necroptosis-inducing signals. Additionally, when cells express a form of RIPK3 which cannot be recognized by CK1, the cells also remain alive. This work defines a step in the necroptosis pathway and identifies potential targets for intervening necroptosis-associated diseases.