cFLIPL acts as a suppressor of TRAIL- and Fas- initiated inflammation by inhibiting assembly of caspase-8/FADD/RIPK1 NF-KB-activating complexes

被引：15

作者：

Davidovich, Pavel ^{[1
]}

Higgins, Catherine A. ^{[2
]}

Najda, Zaneta ^{[1
]}

Longley, Daniel B. ^{[2
]}

Martin, Seamus J. ^{[1
]}

机构：

[1] Trinity Coll Dublin, Smurfit Inst, Mol Cell Biol Lab, Dept Genet, Dublin 2, Ireland

[2] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland

来源：

CELL REPORTS | 2023年 / 42卷 / 12期

基金：

欧洲研究理事会;

关键词：

KAPPA-B ACTIVATION; CELL-DEATH; GENE INDUCTION; CASPASE; 8; C-FLIP; APOPTOSIS; RECEPTORS; FADD; CD95; RIPOPTOSOME;

D O I：

10.1016/j.celrep.2023.113476

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

TRAIL and FasL are potent inducers of apoptosis but can also promote inflammation through assembly of cytoplasmic caspase-8/FADD/RIPK1 (FADDosome) complexes, wherein caspase-8 acts as a scaffold to drive FADD/RIPK1-mediated nuclear factor KB (NF-KB) activation. cFLIP is also recruited to FADDosomes and restricts caspase-8 activity and apoptosis, but whether cFLIP also regulates death receptor-initiated inflammation is unclear. Here, we show that silencing or deletion of cFLIP leads to robustly enhanced Fas-, TRAIL-, or TLR3-induced inflammatory cytokine production, which can be uncoupled from the effects of cFLIP on caspase-8 activation and apoptosis. Mechanistically, cFLIPL suppresses Fasor TRAIL-initiated NF-KB activation through inhibiting the assembly of caspase-8/FADD/RIPK1 FADDosome complexes, due to the low affinity of cFLIPL for FADD. Consequently, increased cFLIPL occupancy of FADDosomes diminishes recruitment of FADD/RIPK1 to caspase-8, thereby suppressing NF-KB activation and inflammatory cytokine production downstream. Thus, cFLIP acts as a dual suppressor of apoptosis and inflammation via distinct modes of action.

引用

页数：23