The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK1

Int J Mol Sci. 2021 May 28;22(11):5796. doi: 10.3390/ijms22115796.


Receptor-interacting protein kinase 1 (RIPK1) is a key component of the tumor necrosis factor (TNF) receptor signaling complex that regulates both pro- and anti-apoptotic signaling. The reciprocal functions of RIPK1 in TNF signaling are determined by the state of the posttranslational modifications (PTMs) of RIPK1. However, the underlying mechanisms associated with the PTMs of RIPK1 are unclear. In this study, we found that RING finger protein 4 (RNF4), a RING finger E3 ubiquitin ligase, is required for the RIPK1 autophosphorylation and subsequent cell death. It has been reported that RNF4 negatively regulates TNF-α-induced activation of the nuclear factor-κB (NF-κB) through downregulation of transforming growth factor β-activated kinase 1 (TAK1) activity, indicating the possibility that RNF4-mediated TAK1 suppression results in enhanced sensitivity to cell death. However, interestingly, RNF4 was needed to induce RIPK1-mediated cell death even in the absence of TAK1, suggesting that RNF4 can promote RIPK1-mediated cell death without suppressing the TAK1 activity. Thus, these observations reveal the existence of a novel mechanism whereby RNF4 promotes the autophosphorylation of RIPK1, which provides a novel insight into the molecular basis for the PTMs of RIPK1.

Keywords: RING finger protein 4 (RNF4); TNF receptor-mediated cell death; Tumor necrosis factor-α (TNF-α); receptor-interacting protein kinase 1 (RIPK1).

MeSH terms

  • Adolescent
  • Animals
  • Apoptosis / drug effects
  • Caspase 8 / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Immunoblotting
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice, Knockout
  • Phosphorylation
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Rnf4 protein, mouse
  • Ubiquitin-Protein Ligases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Caspase 8