Redundant and receptor-specific activities of TRADD, RIPK1 and FADD in death receptor signaling.

Abstract

We evaluated redundant and receptor-specific activities of TRADD, RIPK1, and FADD in RIPK3-expressing HeLa cells lacking expression of these proteins or any combination of two of these factors. We confirmed the opposing role of FADD in TNF- and TRAIL-induced necroptosis and observed an anti-necroptotic function of TRADD. RIPK1 and TRADD act in a redundant manner in TNF- but not TRAIL-induced apoptosis. Complementary, FADD proved to be sufficient for TRAIL- but not for TNF-induced apoptosis. TRADD and RIPK1, however, redundantly mediated proinflammatory signaling in response to TNF and TRAIL. FADD deficiency sensitized more efficiently for TNFR1-mediated necroptosis than caspase-8 deficiency pointing to a caspase-8 independent inhibitory activity of FADD on TNF-induced necroptosis. Based on these characteristics, we propose a model in which the death receptor-specific activities of TRADD, RIPK1, and FADD are traced back to their hierarchically different position in TNFR1- and TRAIL death receptor signaling.

• Authors: Simone Füllsack, Alevtina Rosenthal, Harald Wajant, Daniela Siegmund
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 2 Pg. 122 (02 11 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 30741924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FADD protein, human
• Fas-Associated Death Domain Protein
• NF-kappa B
• Oligopeptides
• TNF Receptor-Associated Death Domain Protein
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha
• benzyloxycarbonyl-valyl-alanyl-aspartic acid
• RIPK1 protein, human
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• Caspase 8

Topics

• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Fas-Associated Death Domain Protein (metabolism)
• HeLa Cells
• Humans
• NF-kappa B (metabolism)
• Oligopeptides (pharmacology)
• Receptor-Interacting Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• TNF Receptor-Associated Death Domain Protein (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)