STAT1 Inhibits NF-κB in TNFα Receptor Signaling

Science's STKE  20 Jun 2000:
Vol. 2000, Issue 37, pp. tw3
DOI: 10.1126/stke.2000.37.tw3

Activation of the TNF-α receptor (TNFR) can lead to programmed cell death or promote cell survival depending on the protein complexes that form with the TNFR1-associated death domain protein (TRADD). STAT1 has been implicated in apoptosis mediated by TNFR; however, the mechanism remains unclear. Wang et al. demonstrate that STAT1 can interfere with the protein machinery responsible for cell sparing, thus directing TNF-α-treated cells toward apoptosis. STAT1 associated with the TNFR1-TRADD protein complex and inhibited the ability of TRADD to interact with RIP and TRAF2, two proteins involved in NF-κB activation and cell survival. Similarly, STAT1 overexpression inhibited NF-κB activation in TNF-α-treated cells. Although STAT1 is phosphorylated in response to TNF-α, STAT1 did not translocate to the nucleus under these conditions. This suggests that the role of STAT1 in TNF-α-mediated apoptosis lies not in gene transactivation but as an adapter or blocking protein localized to the TNFR complex.

Wang, Y., Wu, T.R., Cai, S., Welte, T., and Chin, Y.E. (2000) STAT1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-κB activation. Mol. Cell. Biol. 20: 4505-4512. [Abstract] [Full Text]