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: Silvia Alvarez-Diaz, Christopher P Dillon, Najoua Lalaoui, Maria C Tanzer, Diego A Rodriguez, Ann Lin, Marion Lebois, Razq Hakem, Emma C Josefsson, Lorraine A O'Reilly, John Silke, Warren S Alexander, Douglas R Green, Andreas Strasser
• Journal: Immunity (Immunity) Vol. 45 Issue 3 Pg. 513-526 (09 20 2016) ISSN: 1097-4180 [Electronic] United States
• PMID: 27523270 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Fas-Associated Death Domain Protein
• MLKL protein, mouse
• Protein Kinases
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Caspase 8

Topics

• Animals
• Apoptosis (physiology)
• Autoimmune Diseases (metabolism)
• Caspase 8 (metabolism)
• Cell Death (physiology)
• Fas-Associated Death Domain Protein (metabolism)
• Mice
• Mice, Inbred C57BL
• Necrosis (metabolism)
• Protein Kinases (metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)