Abstract
TNF-like weak inducer of apoptosis (TWEAK) and inhibition of protein synthesis with cycloheximide (CHX) sensitize for poly(I:C)-induced cell death. Notably, although CHX preferentially enhanced poly(I:C)-induced apoptosis, TWEAK enhanced primarily poly(I:C)-induced necroptosis. Both sensitizers of poly(I:C)-induced cell death, however, showed no major effect on proinflammatory poly(I:C) signaling. Analysis of a panel of HeLa-RIPK3 variants lacking TRADD, RIPK1, FADD, or caspase-8 expression revealed furthermore similarities and differences in the way how poly(I:C)/TWEAK, TNF, and TRAIL utilize these molecules for signaling. RIPK1 turned out to be essential for poly(I:C)/TWEAK-induced caspase-8-mediated apoptosis but was dispensable for this response in TNF and TRAIL signaling. TRADD-RIPK1-double deficiency differentially affected poly(I:C)-triggered gene induction but abrogated gene induction by TNF completely. FADD deficiency abrogated TRAIL- but not TNF- and poly(I:C)-induced necroptosis, whereas TRADD elicited protective activity against all three death inducers. A general protective activity against poly(I:C)-, TRAIL-, and TNF-induced cell death was also observed in FLIPL and FLIPS transfectrants.
Highlights
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily (TNFSF)
It is very well established that treatment with cycloheximide (CHX) sensitizes many cell types, including HeLa and HaCaT cells, for death receptor-induced cell death
CHX treatment sensitized HeLa-RIPK3 and HaCaT cells for poly(I:C)induced cell death (Fig. 1a–d), and this cytotoxic response was further enhanced by stimulation with Flag-TNF-like weak inducer of apoptosis (TWEAK) (Fig. 1e)
Summary
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily (TNFSF). TWEAK exerts its biological activities by stimulation of fibroblast growth factor-inducible-14 (Fn14), which is a TRAF2-interacting receptor of the TNF receptor superfamily (TNFRSF)[1]. The TWEAK/ Fn14 system induces pleiotropic cellular activities ranging from proinflammatory gene induction over stimulation of angiogenesis, proliferation, and cellular differentiation to Official journal of the Cell Death Differentiation Association. It is worth mentioning that depletion of TRAF2-cIAP1/2 complexes enables TWEAK to dampen the proinflammatory responses of TNFR1 and other TRAF2 utilizing TNFRSF receptors, e.g., CD409,10. It is noteworthy that pathogen- and damage-associated molecular pattern (PAMP/DAMP)sensing receptors and receptors of the TNFRSF, especially TNFR1, utilize an overlapping set of signaling molecules, including caspase-8, TRAF family members, and the death domain proteins TRADD, FADD, and RIPK114–16
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