HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by O’Donnell, M. A. Articles by Ting, A. PubMed Articles by O’Donnell, M. A. Articles by Ting, A.

Ubiquitination of RIP1 regulates an NF-B-independent cell death switch in TNF signaling.

Immunobiology, Mount Sinai School of Medicine, Immunobiology Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1630, New York, New York, 10029

Abstract

TNF receptor 1 (TNFR1) can trigger opposing responses within the same cell: one leads to a pro-survival response whereas the other leads to cell death. The pro-survival response is mediated primarily by activation of the NF-B signaling pathway, which leads to the expression of pro-survival genes such as c-FLIP, c-IAPs, TRAFs and BCL-2 family members. On the other hand, TNF can also trigger activation of CASPASE 8 and 3 leading eventually to apoptosis. In most cell types, stimulation with TNF does not lead to apoptosis unless NF-B signaling is blocked. Hence, NF-B-mediated transcription of pro-survival genes acts as a cell death switch during TNF signaling. This current study demonstrates the existence of another cell death switch elsewhere in the pathway that is independent of NF-B. Our results show that lysine 63-linked ubiquitination of RIP1 on lysine 377 inhibits TNF-induced apoptosis first through an NF-B-independent mechanism, and subsequently, through an NF-B-dependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a pro-apoptotic signaling molecule. Therefore, RIP1 is a dual-function molecule that can be either pro-survival or pro-death depending on its ubiquitination state and this serves as an NF-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, which was previously implicated to be both pro-survival and pro-death. Since TRAF2 is the E3 ligase for RIP1, these observations also provide an explanation for the NF-B-independent anti-apoptotic function of TRAF2 previously described.

This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by O’Donnell, M. A. Articles by Ting, A. PubMed Articles by O’Donnell, M. A. Articles by Ting, A.