Journal article
The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis
S Alvarez-Diaz, CP Dillon, N Lalaoui, MC Tanzer, DA Rodriguez, A Lin, M Lebois, R Hakem, EC Josefsson, LA O'Reilly, J Silke, WS Alexander, DR Green, A Strasser
Immunity | CELL PRESS | Published : 2016
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..
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Awarded by National Institute of Allergy and Infectious Diseases
Funding Acknowledgements
We thank J. Lochland and C. Hall for genotyping, J.G. Zhang for FASL, M. Yang for technical assistance, and S. Hedrick (UC) for Casp8<SUP>-/-</SUP> mice. S.A.-D. was supported by a Spanish Ministry of Education Postdoctoral Fellowship. M.C.T. was supported by a Victorian International Research Scholarship. This work was funded by grants and fellowships from the National Health and Medical Research Council (NHMRC) (1016647, 1058344, 1079250, 1047672, 1025594, 1057905, and 1046984), the Australian Cancer Research Fund, the U.S. NIH, and the American Lebanese Syrian Associated Charities. This work made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (361646).