The e3 ubiquitin-protein ligase rnf4 promotes tnf-α-induced cell death triggered by ripk1

Tatsuya Shimada, Yuki Kudoh, Takuya Noguchi, Tomohiro Kagi, Midori Suzuki, Mei Tsuchida, Hiromu Komatsu, Miki Takahashi, Yusuke Hirata, Atsushi Matsuzawa

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Article number5796
JournalInternational journal of molecular sciences
Issue number11
Publication statusPublished - 2021 Jun 1


  • RING finger protein 4 (RNF4)
  • Receptor-interacting protein kinase 1 (RIPK1)
  • TNF receptor-mediated cell death
  • Tumor necrosis factor-α (TNF-α)

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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