Journal
CURRENT BIOLOGY
Volume 17, Issue 5, Pages 418-424Publisher
CELL PRESS
DOI: 10.1016/j.cub.2007.01.027
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Funding
- NIAID NIH HHS [R01 AI052417, R21 AI057997, R01 AI 52417] Funding Source: Medline
- PHS HHS [R21 57997] Funding Source: Medline
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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-kappa B-mediated transcription of prosurvival genes [3-9]; apoptosis occurs if NF-kappa B signaling is blocked [5,7-9]. Hence, activation of NF-kappa B 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-kappa B. We show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-kappa B-independent mechanism and, subsequently, through an NF-kappa B-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-kappa B-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-kappa B-independent antiapoptotic function previously described for TRAF2 [14-16].
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