Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death

Tumor necrosis factor (TNF) signaling leads to pleiotropic responses in a w ide range of cell types, in part by activating antiapoptotic and proapoptot ic pathways. Previous studies have suggested that TNF receptor-associated f actor (TRAF) 2 can mediate crucial antiapoptotic signals during TNF stimula tion. However, it is unclear how the antiapoptotic signals via TRAF2 in TNF -R1 signaling is regulated. Here we show that TRAF1 is cleaved by caspase-8 into two fragments during apoptosis induced by TNF, Overexpression of the C-terminal cleavage product, TRAF1-c, increased TNF-induced cell death of h ybridoma T cells. Importantly, we demonstrate that the cleavage product of TRAF1 coimmunoprecipitates with TRAF2 that is released from the TNF-R1 comp lex in response to prolonged TNF treatment. These results indicate that cas pase-dependent cleavage of TRAF1 generates TRAF1-c fragments that are able to bind TRAF2, and then sequester TRAF2 from the TNF-R1 complex, rendering cells, at least in part, sensitive to TNF. (C) 2001 Academic Press.