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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.

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.

journal_name

Immunity

journal_title

Immunity

authors

Alvarez-Diaz S,Dillon CP,Lalaoui N,Tanzer MC,Rodriguez DA,Lin A,Lebois M,Hakem R,Josefsson EC,O'Reilly LA,Silke J,Alexander WS,Green DR,Strasser A

doi

10.1016/j.immuni.2016.07.016

subject

Has Abstract

pub_date

2016-09-20 00:00:00

pages

513-526

issue

3

eissn

1074-7613

issn

1097-4180

pii

S1074-7613(16)30289-8

journal_volume

45

pub_type

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