RNF4 Is a poly-SUMO-specific E3 Ubiquitin Ligase Required for Arsenic-Induced PML Degradation

Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13.

Abstract

In acute promyelocytic leukaemia (APL), the promyelocytic leukaemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). This disease can be treated effectively with arsenic, which induces PML modification by small ubiquitin-like modifiers (SUMO) and proteasomal degradation. Here we demonstrate that the RING-domain-containing ubiquitin E3 ligase, RNF4 (also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. RNF4 depletion or proteasome inhibition led to accumulation of mixed, polyubiquitinated, poly-SUMO chains. PML protein accumulated in RNF4-depleted cells and was ubiquitinated by RNF4 in a SUMO-dependent fashion in vitro. In the absence of RNF4, arsenic failed to induce degradation of PML and SUMO-modified PML accumulated in the nucleus. These results demonstrate that poly-SUMO chains can act as discrete signals from mono-SUMOylation, in this case targeting a poly-SUMOylated substrate for ubiquitin-mediated proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arsenic / metabolism*
  • Cell Line
  • Humans
  • Leukemia, Promyelocytic, Acute / genetics
  • Leukemia, Promyelocytic, Acute / metabolism
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Promyelocytic Leukemia Protein
  • Proteasome Endopeptidase Complex / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Sequence Alignment
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Neoplasm Proteins
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Promyelocytic Leukemia Protein
  • RNA, Small Interfering
  • RNF4 protein, human
  • SUMO-1 Protein
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • PML protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Arsenic