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.
Highlights
The death domain (DD) has been originally recognized due to its relevance for apoptosis induction by CD95 (Fas/ APO-1) and tumor necrosis factor (TNF) receptor 1 (TNFR1)[1,2], but is present in the CD95-related death receptors TNF-related death-inducing ligand (TRAIL) receptor 1 (TRAILR1, called death receptor 4 (DR4)) and TRAILR2/DR5
The huge majority of studies revealed an essential role of Fas associated death domain protein (FADD) in caspase activation and apoptosis induction by TNFR1, CD95, and the TRAIL death receptors[11,12,13,14,15,16,17]
It appeared that TNF and TRAIL-induced processing of caspase-8 and caspase[8] substrates such as CYLD and RIPK1 is enhanced in the CHX-sensitized HeLa-RIPK3 cells (Fig. 1a)
Summary
The death domain (DD) has been originally recognized due to its relevance for apoptosis induction by CD95 (Fas/ APO-1) and tumor necrosis factor (TNF) receptor 1 (TNFR1)[1,2], but is present in the CD95-related death receptors TNF-related death-inducing ligand (TRAIL) receptor 1 (TRAILR1, called death receptor 4 (DR4)) and TRAILR2/DR5 (ref. 3). TRADD, FADD, and RIPK1 have all been implicated in signaling by each of the mentioned DD-. The huge majority of studies revealed an essential role of FADD in caspase activation and apoptosis induction by TNFR1, CD95, and the TRAIL death receptors[11,12,13,14,15,16,17]. FADD is of differential relevance for nuclear factor of kappaB (NFκB) signaling and necroptosis induction by death receptors. With respect to activation of NFκB transcription factors by CD95 and the TRAIL death receptors, FADD has been found to be an essential factor while it is dispensable for this response in the case of TNFR119–23.
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