The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation

Abstract

Many diverse activities of tumor necrosis factor (TNF) are signaled through TNF receptor 1 (TNFR1). We have identified a novel 34 kDa protein, designated TRADD, that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa B. The C-terminal 118 amino acids of TRADD are sufficient to trigger both of these activities and likewise sufficient for interaction with the death domain of TNFR1. TRADD-mediated cell death can be suppressed by the crmA gene, which encodes a specific inhibitor of the interleukin-1 beta-converting enzyme. However, NF-kappa B activation by TRADD is not inhibited by crmA expression, demonstrating that the signaling pathways for TNF-induced cell death and NF-kappa B activation are distinct.

From receptors to stress-activated MAP kinases

“…TNF binding induces receptor aggregation, which results in the recruitment of a number of cytoplasmic signaling proteins to two distinct TNFR complexes (Rothe et al, 1994(Rothe et al, , 1995bHsu et al, 1995Hsu et al, , 1996aShu et al, 1996). One of these molecules is TNF receptor associated factor 2 Figure 1 The mammalian stress-activated MAP kinase modules.…”

“…One of these molecules is TNF receptor associated factor 2 Figure 1 The mammalian stress-activated MAP kinase modules. The question marks indicate that direct evidence of these pathways remain to be established (TRAF2), which interacts directly with TNFR-2 (Rothe et al, 1994) but is recruited to TNFR-1 via its interaction with TNFR-1-associated death domain protein (TRADD; Hsu et al, 1995Hsu et al, , 1996b. To date, six members of the TRAF family have been identi®ed (Hu et al, 1994;Rothe et al, 1994;Cheng et al, 1995;Mosialos et al, 1995;Re gnier et al, 1995;Cao et al, 1996;Nakano et al, 1996).…”

Body language: the function of PML nuclear bodies in apoptosis regulation

“…70 In the nuclear compartment, TRADD is found in association with PML-NBs. 87 The isolated DD of TRADD, which also mediates the interaction with the TNF-R1 DD, 70,88 is responsible for PML-NB localisation and is sufficient to initiate a caspaseindependent form of cell death. Apoptosis through TRADD-DD overexpression is in part inhibited by Bcl-X L , a mitochondria-localised antiapoptotic member of the Bcl-2 protein family, and relies on p53 and PML expression.…”

MyD genes in negative growth control

“…The TNFR1 complex was shown to recruit the death domain-containing molecule TRADD (Hsu et al, 1995), which mediates NF-kB activation and apoptosis. To activate NF-kB, TRADD interacts with serine/threonine kinase RIP and TRAF2, that are linked to the NIK/IkK cascade, and trigger the phosphorylation and degradation of IkB (Hsu et al, 1996a,b).…”