| First Author | O'Donnell MA | Year | 2007 |
| Journal | Curr Biol | Volume | 17 |
| Issue | 5 | Pages | 418-24 |
| PubMed ID | 17306544 | Mgi Jnum | J:120727 |
| Mgi Id | MGI:3707902 | Doi | 10.1016/j.cub.2007.01.027 |
| Citation | O'Donnell MA, et al. (2007) Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol 17(5):418-24 |
| abstractText | 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-kappaB-mediated transcription of prosurvival genes [3-9]; apoptosis occurs if NF-kappaB signaling is blocked [5, 7-9]. Hence, activation of NF-kappaB 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-kappaB. We show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-kappaB-independent mechanism and, subsequently, through an NF-kappaB-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-kappaB-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-kappaB-independent antiapoptotic function previously described for TRAF2 [14-16]. |
