title: The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis.
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.
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Silvia
authors: S
authors: Alvarez-Diaz
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Christopher P
authors: CP
authors: Dillon
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Najoua
authors: N
authors: Lalaoui
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Maria C
authors: MC
authors: Tanzer
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Diego A
authors: DA
authors: Rodriguez
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors: Ann
authors: A
authors: Lin
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors: Marion
authors: M
authors: Lebois
authors: Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors: Razq
authors: R
authors: Hakem
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Emma C
authors: EC
authors: Josefsson
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Lorraine A
authors: LA
authors: O'Reilly
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: John
authors: J
authors: Silke
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia. Electronic address: alexandw@wehi.edu.au.
authors: Warren S
authors: WS
authors: Alexander
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
authors: Douglas R
authors: DR
authors: Green
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia. Electronic address: strasser@wehi.edu.au.
authors: Andreas
authors: A
authors: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001327:Autoimmune Diseases / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D053200:Fas-Associated Death Domain Protein; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8