title: FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis.
abstract: Tumor Necrosis Factor-α canonically induces the activation of NF-κB and associated gene product cellular FLICE-like inhibitory protein (cFLIPL) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIPL 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-κB 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 cFLIPL and inhibition of NF-κB activation, independent of TNF-α stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIPL 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 cFLIPL that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival.
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar-382007, Gujarat, India.
authors.forename: Kishu
authors.initials: K
authors.lastname: Ranjan
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar-382007, Gujarat, India.
authors.forename: Chandramani
authors.initials: C
authors.lastname: Pathak
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011485:Protein Binding; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; C432966:ITCH protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8