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

Curr Biol. 2007 Mar 6;17(5):418-24. doi: 10.1016/j.cub.2007.01.027. Epub 2007 Feb 15.

Abstract

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].

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Gene Expression Regulation*
  • Humans
  • Jurkat Cells
  • Lysine / chemistry
  • NF-kappa B / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitins / metabolism*

Substances

  • NF-kappa B
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Ubiquitins
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Lysine