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The pseudokinase MLKL and the kinase RIPK3 have distinct roles in autoimmune disease caused by loss of death-receptor-induced apoptosis


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
2016-08-10
Immunity
Journal Article
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.
Cell Press
Molecular Immunology; Cell Signalling and Cell Death; Molecular Genetics of Cancer; Cancer and Haematology
10.1016/j.immuni.2016.07.016
27523270
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2016-08-19 02:01:09 Last Modified 2018-07-09 03:21:03