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

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.

Soluble TNF-like weak inducer of apoptosis (TWEAK) enhances poly(I:C)-induced RIPK1-mediated necroptosis.

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.

TWEAK inhibits TRAF2-mediated CD40 signaling by destabilization of CD40 signaling complexes.

We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-κB signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF-κB pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)-induced activation of MAPKs in TWEAK-primed cells.

Fibroblast growth factor inducible (Fn14)-specific antibodies concomitantly display signaling pathway-specific agonistic and antagonistic activity.

Background: Fn14 is a therapeutic target in various diseases.

Results: Anti-Fn14 antibodies activate the alternative NFκB pathway but not other Fn14-related activities induced by soluble or membrane-bound TWEAK. FcγR-bound anti-Fn14 antibodies, however, activate the full spectrum of Fn14-associated activities.