CRL2-KLHDC3 E3 ubiquitin ligase complex suppresses ferroptosis through promoting p14ARF degradation

Cell Death Differ. 2022 Apr;29(4):758-771. doi: 10.1038/s41418-021-00890-0. Epub 2021 Nov 6.

Abstract

The cystine/glutamate antiporter SLC7A11 (commonly known as xCT) functions to import cystine for glutathione biosynthesis, thereby protecting cells from oxidative stress and ferroptosis, a regulated form of non-apoptotic cell death driven by the accumulation of lipid-based reactive oxygen species (ROS). p14ARF, a well-established tumor suppressor, promotes ferroptosis by inhibiting NRF2-mediated SLC7A11 transcription. Here, we demonstrate the crucial role of Cullin 2 RING E3 ligase (CRL2)-KLHDC3 E3 ubiquitin ligase complex in regulating p14ARF protein stability. KLHDC3 acts as a CRL2 adaptor that specifically recognizes a C-terminal degron in p14ARF and triggers p14ARF for ubiquitin-proteasomal degradation. This regulation mode is absent in the murine p14ARF homolog, p19arf which lacks the C-terminal degron. We also show that KLHDC3 suppresses ferroptosis in vitro and supports tumor growth in vivo by relieving p14ARF-mediated suppression of SLC7A11 transcription. Overall, these findings reveal that the protein stability and pro-ferroptotic function of p14ARF are controlled by a CRL2 E3 ubiquitin ligase complex, and suggest that suppression of the p14ARF-NRF2-SLC7A11 regulatory pathway by KLHDC3 overexpression likely contributes to cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cystine
  • Ferroptosis*
  • Mice
  • Tumor Suppressor Protein p14ARF* / metabolism
  • Ubiquitin-Protein Ligases* / genetics

Substances

  • Cell Cycle Proteins
  • Klhdc3 protein, mouse
  • Tumor Suppressor Protein p14ARF
  • Cystine
  • Ubiquitin-Protein Ligases