Ubiquitin-specific Protease 11 (USP11) Deubiquitinates Hybrid Small Ubiquitin-like Modifier (SUMO)-Ubiquitin Chains to Counteract RING Finger Protein 4 (RNF4)

J Biol Chem. 2015 Jun 19;290(25):15526-15537. doi: 10.1074/jbc.M114.618132. Epub 2015 May 12.

Abstract

Ring finger protein 4 (RNF4) is a SUMO-targeted ubiquitin E3 ligase with a pivotal function in the DNA damage response (DDR). SUMO interaction motifs (SIMs) in the N-terminal part of RNF4 tightly bind to SUMO polymers, and RNF4 can ubiquitinate these polymers in vitro. Using a proteomic approach, we identified the deubiquitinating enzyme ubiquitin-specific protease 11 (USP11), a known DDR-component, as a functional interactor of RNF4. USP11 can deubiquitinate hybrid SUMO-ubiquitin chains to counteract RNF4. SUMO-enriched nuclear bodies are stabilized by USP11, which functions downstream of RNF4 as a counterbalancing factor. In response to DNA damage induced by methyl methanesulfonate, USP11 could counteract RNF4 to inhibit the dissolution of nuclear bodies. Thus, we provide novel insight into cross-talk between ubiquitin and SUMO and uncover USP11 and RNF4 as a balanced SUMO-targeted ubiquitin ligase/protease pair with a role in the DDR.

Keywords: DNA damage response; RING finger protein 4 (RNF4); USP11; deubiquitylation (deubiquitination); proteasome; small ubiquitin-like modifier (SUMO); sumoylation; ubiquitin; ubiquitin-dependent protease; ubiquitylation (ubiquitination).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • HeLa Cells
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / physiology*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*

Substances

  • Nuclear Proteins
  • RNF4 protein, human
  • SUMO-1 Protein
  • Transcription Factors
  • USP11 protein, human
  • Ubiquitins
  • Ubiquitin-Protein Ligases
  • Thiolester Hydrolases