期刊
CELL REPORTS
卷 16, 期 12, 页码 3247-3259出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.06.103
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类别
资金
- National Natural Science Foundation of China [31571426, 81502548]
- Thousand Young Talents Program of the Chinese government
MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-) Mlkl(-/-) mice are viable and fertile. Mlkl(-/-) Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-) Fadd(-/-) mice. Mlkl(-/-) Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-kappa B-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome.
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