Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep22787
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Funding
- Department of Biotechnology, Ministry of Science & Technology, Govt. of India [BT/PR15083/GBD/27/306/2011, 6242/P60/RGCB/PMD/DBT/CMPK/2015]
- Department of Science and Technology, Govt. of India [SR/FT/LS-59/2010]
- GSBTM, Department of Science and Technology, Govt. of Gujarat, India [GSBTM/MD/PROJECTS/SSA/1410/2014-15]
- Indian Council of Medical Research, Govt. of India
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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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