The pseudokinase MLKL and the kinase RIPK3 have distinct roles in autoimmune disease caused by loss of death-receptor-induced apoptosis
- Author(s)
- Alvarez-Diaz, S; Dillon, CP; Lalaoui, N; Tanzer, MC; Rodriguez, DA; Lin, A; Lebois, M; Hakem, R; Josefsson, EC; O'Reilly, LA; Silke, J; Alexander, WS; Green, DR; Strasser, A;
- Journal Title
- Immunity
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- Cell Press
- Research Division(s)
- Molecular Genetics Of Cancer; Molecular Immunology; Cell Signalling And Cell Death; Cancer And Haematology
- PubMed ID
- 27523270
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2016.07.016
- NHMRC Grants
- NHMRC/1016647, NHMRC/1058344, NHMRC/1079250, NHMRC/1047672, NHMRC/1025594, NHMRC/1057905, NHMRC/1046984,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-08-19 02:01:09
Last Modified: 2018-07-09 03:21:03