Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling

TNF receptor 1 (TNFR1) can trigger opposing responses within the same cell: a prosurvival response or a cell-death pathway [1, 2]. Cell survival requires NF-kB-mediated transcription of prosurvival genes [3–9]; apoptosis occurs if NF-kB signaling is blocked [5, 7–9]. Hence, activation of NF-kB acts as a cell-death switch during TNF signaling. This study demonstrates that the pathway includes another cell-death switch that is independent of NF-kB. We show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-kB-independent mechanism and, subsequently, through an NF-kB-dependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a proapoptotic signaling molecule by engaging CASPASE-8. Therefore, RIP1 is a dual-function molecule that can be either prosurvival or prodeath depending on its ubiquitination state, and this serves as an NF-kB-independent cell-death switch early in TNF signaling. These results provide an explanation for the conflicting reports on the role of RIP1 in cell death; this role was previously suggested to be both prosurvival and prodeath [10–12]. Because TRAF2 is the E3 ligase for RIP1 [13], these observations provide an explanation for the NF-kB-independent antiapoptotic function previously described for TRAF2 [14–16].