The pseudokinase MLKL and the kinase RIPK3 have distinct roles in autoimmune disease caused by loss of death-receptor-induced apoptosis
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
WEHI Research Division(s)
Molecular Genetics Of Cancer; Molecular Immunology; Cell Signalling And Cell Death; Cancer And Haematology
PubMed ID
27523270
Terms of Use/Rights Notice
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Creation Date: 2016-08-19 02:01:09
Last Modified: 2018-07-09 03:21:03
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