TY - JOUR
T1 - Ubiquitination of RIP1 Regulates an NF-κB-Independent Cell-Death Switch in TNF Signaling
AU - O'Donnell, Marie Anne
AU - Legarda-Addison, Diana
AU - Skountzos, Penelopi
AU - Yeh, Wen Chen
AU - Ting, Adrian T.
N1 - Funding Information:
We are very grateful to Drs. Zhijian Chen (University of Texas Southwestern), Paul Leibson (Mayo Clinic), and Brian Seed (Massachusetts General Hospital) for providing critical reagents. We would also like to thank Dr. Michelle Kelliher and Yibin Yang (University of Massachusetts, Worchester) for sharing data, and Drs. Ben Chen, Jay Unkeless, and Ramnik Xavier for critical reading of the manuscript. This work was supported by National Institutes of Health grants R21-57997 and R01-AI52417 (A.T.T.) and was aided by a grant from the New York Chapter of the Arthritis Foundation (A.T.T.). M.A.O'D. is a recipient of a Research Fellowship Award from the Crohn's and Colitis Foundation of America. W.C.Y. is an employee of Amgen, Inc.
PY - 2007/3/6
Y1 - 2007/3/6
N2 - 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-κB-mediated transcription of prosurvival genes [3-9]; apoptosis occurs if NF-κB signaling is blocked [5, 7-9]. Hence, activation of NF-κB 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-κB. We show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-κB-independent mechanism and, subsequently, through an NF-κB-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-κB-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-κB-independent antiapoptotic function previously described for TRAF2 [14-16].
AB - 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-κB-mediated transcription of prosurvival genes [3-9]; apoptosis occurs if NF-κB signaling is blocked [5, 7-9]. Hence, activation of NF-κB 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-κB. We show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-κB-independent mechanism and, subsequently, through an NF-κB-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-κB-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-κB-independent antiapoptotic function previously described for TRAF2 [14-16].
KW - CELL CYCLE
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=33847251527&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847251527&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2007.01.027
DO - 10.1016/j.cub.2007.01.027
M3 - Article
C2 - 17306544
AN - SCOPUS:33847251527
SN - 0960-9822
VL - 17
SP - 418
EP - 424
JO - Current Biology
JF - Current Biology
IS - 5
ER -