Cell fate decisions regulated by K63 ubiquitination of tumor necrosis factor receptor 1

Mol Cell Biol. 2014 Sep;34(17):3214-28. doi: 10.1128/MCB.00048-14. Epub 2014 Jun 30.

Abstract

Signaling by tumor necrosis factor (TNF) receptor 1 (TNF-R1), a prototypic member of the death receptor family, mediates pleiotropic biological outcomes ranging from inflammation and cell proliferation to cell death. Although many elements of specific signaling pathways have been identified, the main question of how these selective cell fate decisions are regulated is still unresolved. Here we identified TNF-induced K63 ubiquitination of TNF-R1 mediated by the ubiquitin ligase RNF8 as an early molecular checkpoint in the regulation of the decision between cell death and survival. Downmodulation of RNF8 prevented the ubiquitination of TNF-R1, blocked the internalization of the receptor, prevented the recruitment of the death-inducing signaling complex and the activation of caspase-8 and caspase-3/7, and reduced apoptotic cell death. Conversely, recruitment of the adaptor proteins TRADD, TRAF2, and RIP1 to TNF-R1, as well as activation of NF-κB, was unimpeded and cell growth and proliferation were significantly enhanced in RNF8-deficient cells. Thus, K63 ubiquitination of TNF-R1 can be sensed as a new level of regulation of TNF-R1 signaling at the earliest stage after ligand binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Caspase 8 / metabolism
  • Cell Line
  • Cell Survival / physiology
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endocytosis
  • Fas-Associated Death Domain Protein / metabolism
  • HeLa Cells
  • Humans
  • Mice
  • Models, Biological
  • Nuclear Pore Complex Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / chemistry*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • U937 Cells
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination*

Substances

  • AGFG1 protein, human
  • DNA-Binding Proteins
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Nuclear Pore Complex Proteins
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • RNF8 protein, human
  • Receptors, Tumor Necrosis Factor, Type I
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Ube2n protein, mouse
  • Ubiquitin-Conjugating Enzymes
  • Rnf8 protein, mouse
  • Ubiquitin-Protein Ligases
  • CASP8 protein, human
  • Caspase 8