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The activation of the transcription factor NF-kappaB often results in protection against apoptosis. In particular, pro-apoptotic tumor necrosis factor (TNF) signals are blocked by proteins that are induced by NF-kappaB such as TNFR-associated factor 1 (TRAF1). Here we show that TRAF1 is cleaved after Asp-163 when cells are induced to undergo apoptosis by Fas ligand (FasL). The C-terminal cleavage product blocks the induction of NF-kappaB by TNF and therefore functions as a dominant negative (DN) form of TRAF1. Our results suggest that the generation of DN-TRAF1 is part of a pro-apoptotic amplification system to assure rapid cell death.

Tumor necrosis factor receptor (TNFR)-associated factor TRAF1 was first identified as a component of the TNFR2 signalling complex. Unlike the other members of the TRAF family, TRAF1 lacks the N-terminal ring finger motif and has a tissue specific expression. Here we demonstrate that expression of TRAF1 is induced by TNF and the protein kinase C (PKC) activator PMA, but not by interleukin-1 (IL-1). TNF-induced upregulation of TRAF1 could be prevented by pretreatment of the cells with the proteasome inhibitor MG-132, whereas the PKC inhibitor Ro31-8220 was without effect. Interestingly, overexpression of TRAF1 in HEK293T completely prevented NF-κB activation induced by TNF, IL-1, or overexpression of TRAF2 or TRAF6. These data suggest that inducible expression of TRAF1 may serve a negative regulatory function in NF-κB signalling pathways.