The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis

The kinases RIPK1 and RIPK3 and the pseudo-kinase MLKL have been identified as key regulators of the necroptotic cell death pathway, although a role for MLKL within the whole animal has not yet been established. Here, we have shown that MLKL deficiency rescued the embryonic lethality caused by loss of Caspase-8 or FADD. Casp8−/−Mlkl−/− and Fadd−/−Mlkl−/− mice were viable and fertile but rapidly developed severe lymphadenopathy, systemic autoimmune disease, and thrombocytopenia. These morbidities occurred more rapidly and with increased severity in Casp8−/−Mlkl−/− and Fadd−/−Mlkl−/− mice compared to Casp8−/−Ripk3−/− or Fadd−/−Ripk3−/− mice, respectively. These results demonstrate that MLKL is an essential effector of aberrant necroptosis in embryos caused by loss of Caspase-8 or FADD. Furthermore, they suggest that RIPK3 and/or MLKL may exert functions independently of necroptosis. It appears that non-necroptotic functions of RIPK3 contribute to the lymphadenopathy, autoimmunity, and excess cytokine production that occur when FADD or Caspase-8-mediated apoptosis is abrogated. •MLKL is an essential effector of necroptosis in vivo•RIPK3 exacerbates the development and progression of ALPS-like disease•RIPK3 and maybe MLKL exert additional functions beyond inducing cell death Necroptosis is a form of regulated cell death implicated in several pathologies. MLKL was shown to be critical for necroptosis in vitro. Alvarez-Diaz et al. demonstrate that MLKL, like RIPK3, is essential for necroptosis in vivo and reveal that RIPK3 also has a role beyond cell death in promoting lymphadenopathy and autoimmune disease.