Oxidative stress-induced assembly of PML nuclear bodies controls sumoylation of partner proteins

J Cell Biol. 2014 Mar 17;204(6):931-45. doi: 10.1083/jcb.201305148.

Abstract

The promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are stress-responsive domains where many partner proteins accumulate. Here, we clarify the basis for NB formation and identify stress-induced partner sumoylation as the primary NB function. NB nucleation does not rely primarily on intermolecular interactions between the PML SUMO-interacting motif (SIM) and SUMO, but instead results from oxidation-mediated PML multimerization. Oxidized PML spherical meshes recruit UBC9, which enhances PML sumoylation, allow partner recruitment through SIM interactions, and ultimately enhance partner sumoylation. Intermolecular SUMO-SIM interactions then enforce partner sequestration within the NB inner core. Accordingly, oxidative stress enhances NB formation and global sumoylation in vivo. Some NB-associated sumoylated partners also become polyubiquitinated by RNF4, precipitating their proteasomal degradation. As several partners are protein-modifying enzymes, NBs could act as sensors that facilitate and confer oxidative stress sensitivity not only to sumoylation but also to other post-translational modifications, thereby explaining alterations of stress response upon PML or NB loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • COS Cells
  • Cell Nucleus / metabolism
  • Cellular Senescence
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • HeLa Cells
  • Humans
  • Mice
  • Nuclear Proteins / metabolism*
  • Oxidative Stress*
  • Promyelocytic Leukemia Protein
  • Protein Transport
  • Reactive Oxygen Species / metabolism
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation*
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases

Substances

  • Nuclear Proteins
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Reactive Oxygen Species
  • Small Ubiquitin-Related Modifier Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin-Conjugating Enzymes
  • Rnf4 protein, mouse
  • Ubiquitin-Protein Ligases
  • ubiquitin-conjugating enzyme UBC9