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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, Silvia; Dillon, Christopher P; Lalaoui, Najoua; Tanzer, Maria C; Rodriguez, Diego A; Lin, Ann; Lebois, Marion; Hakem, Razq; Josefsson, Emma C; O'Reilly, Lorraine A; Silke, John; Alexander, Warren S; Green, Douglas R; Strasser, Andreas.
Afiliación
  • Alvarez-Diaz S; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  • Dillon CP; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Lalaoui N; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  • Tanzer MC; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  • Rodriguez DA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Lin A; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
  • Lebois M; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
  • Hakem R; Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • Josefsson EC; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  • O'Reilly LA; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  • Silke J; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
  • Alexander WS; 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.
  • Green DR; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
  • Strasser A; 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.
Immunity ; 45(3): 513-526, 2016 09 20.
Article en En | MEDLINE | ID: mdl-27523270
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Quinasas / Enfermedades Autoinmunes / Muerte Celular / Apoptosis / Proteína Serina-Treonina Quinasas de Interacción con Receptores / Proteína de Dominio de Muerte Asociada a Fas Límite: Animals Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Quinasas / Enfermedades Autoinmunes / Muerte Celular / Apoptosis / Proteína Serina-Treonina Quinasas de Interacción con Receptores / Proteína de Dominio de Muerte Asociada a Fas Límite: Animals Idioma: En Año: 2016 Tipo del documento: Article