Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites (Cell Chemical Biology)

McNamara et al. demonstrate that MLKL is extensively auto-inhibited and that several inositol phosphates and their enzymes, but not the putative lipid ligand phosphatidylinositol-4,5-bisphosphate, are required for MLKL activation in necroptosis. These inositol phosphates cooperate with RIPK3 phosphorylation potently activating MLKL to rupture the plasma membrane in necroptosis.