FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis

被引:42
作者
Ranjan, Kishu [1 ]
Pathak, Chandramani [1 ]
机构
[1] Indian Inst Adv Res, Dept Cell Biol, Sch Biol Sci & Biotechnol, Koba Inst Area, Gandhinagar 382007, Gujarat, India
来源
SCIENTIFIC REPORTS | 2016年 / 6卷
关键词
TUMOR-NECROSIS-FACTOR; C-FLIP; REACTIVE OXYGEN; JNK ACTIVATION; DEATH DOMAIN; CELL-DEATH; MEDIATED APOPTOSIS; SIGNALING PATHWAY; CANCER-CELLS; PROTEIN FADD;
D O I
10.1038/srep22787
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Tumor Necrosis Factor-alpha canonically induces the activation of NF-kappa B and associated gene product cellular FLICE-like inhibitory protein (cFLIP(L)) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIP(L) and transduces caspases-8 mediated apoptosis, independent of FasL stimulation in HEK 293T cells. However, the underlying molecular mechanism of FADD mediated ablation of cFLIP and NF-kappa B signaling to determining the fate of cell death or survival remains elusive. Here, we explored a novel molecular mechanism of FADD mediated apoptotic cell death that was directed by ubiquitination of cFLIP(L) and inhibition of NF-kappa B activation, independent of TNF-alpha stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIP(L) to from the death inducing signaling complex (DISC). In addition, FADD negatively regulates cellular inhibitor of apoptosis protein 2 (cIAP2) and Bcl-2. Furthermore, FADD restrains cIAP2 expression and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Interestingly, FADD was also found to promote JNK1 mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIP(L) that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival.
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页数:16
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