Sci. STKE, 13 March 2007
Cell Survival Ubiquitination Controls Life or Death
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005, USA
Tumor necrosis factor (TNF) can trigger cell death or cell survival depending on the context into which the cell receives the signal. O'Donnell et al. show that if lysine 63 ubiquitination of receptor-interacting protein 1 (RIP1) was prevented in Jurkat T cells, the cells exhibited enhanced apoptosis in response to TNF when compared with TNF-treated cells expressing wild-type RIP1. RIP1 ubiquitination was blocked either by expression of a RIP mutant or by expression of dominant-negative forms of the ubiquitin-ligating enzymes TRAF2 (an E3 ubiquitin ligase) or UBC13 (an E2 ubiquitin-conjugating enzyme). The increase in apoptosis did not involve reduced signaling through the nuclear factor B pathway. Cells expressing wild-type RIP1 exhibited the least apoptosis, whereas cells that were expressing RIP1 and in which TRAF2 activity was inhibited exhibited the most apoptosis, which suggests that the ubiquitination state of RIP1 dictates whether it will generate a proapoptotic signal or a prosurvival signal. RIP1 stimulates apoptosis by activation of caspase 8, and in the RIP1 ubiquitination mutant, RIP1 exhibited increased stimulus-dependent association with procaspase 8. The cells expressing the RIP1 ubiquitination mutant showed increased caspase 8 processing. Thus, ubiquitination of RIP1 appears to prevent its interaction with caspase 8. These results provide an explanation for the conflicting roles assigned to RIP1, as both a proapoptotic and prosurvival mediator. Lysine 63 ubiquitination of RIP1 by TRAF2 switches RIP1 from sending a proapoptotic signal to providing a prosurvival signal.
M. A. O'Donnell, D. Legarda-Addison, P. Skountzos, W. C. Yeh, A. T. Ting, Ubiquitination of RIP1 regulates an NF-B-independent cell-death switch in TNF signaling. Curr. Biol. 17, 418-424 (2007). [PubMed]
Citation: N. R. Gough, Ubiquitination Controls Life or Death. Sci. STKE 2007, tw82 (2007).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882