The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes

Andrew M. Pickering, Alison L. Koop, Cheryl Y. Teoh, Gennady Ermak, Tilman Grune, Kelvin J.A. Davies

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

Oxidized cytoplasmic and nuclear proteins are normally degraded by the proteasome, but accumulate with age and disease. We demonstrate the importance of various forms of the proteasome during transient (reversible) adaptation (hormesis), to oxidative stress in murine embryonic fibroblasts. Adaptation was achieved by 'pre-treatment' with very low concentrations of H2O 2, and tested by measuring inducible resistance to a subsequent much higher 'challenge' dose of H2O2. Following an initial direct physical activation of preexisting proteasomes, the 20S proteasome, immunoproteasome and PA28αβ regulator all exhibited substantially increased de novo synthesis during adaptation over 24 h. Cellular capacity to degrade oxidatively damaged proteins increased with 20S proteasome, immunoproteasome and PA28αβ synthesis, and was mostly blocked by the 20S proteasome, immunoproteasome and PA28 siRNA (short interfering RNA) knockdown treatments. Additionally, PA28αβ-knockout mutants achieved only half of the H2O2-induced adaptive increase in proteolytic capacity of wildtype controls. Direct comparison of purified 20S proteasome and immunoproteasome demonstrated that the immunoproteasome can selectively degrade oxidized proteins. Cell proliferation and DNA replication both decreased, and oxidized proteins accumulated, during high H 2O2 challenge, but prior H2O2 adaptation was protective. Importantly, siRNA knockdown of the 20S proteasome, immunoproteasome or PA28αβ regulator blocked 50-100% of these adaptive increases in cell division and DNA replication, and immunoproteasome knockdown largely abolished protection against protein oxidation.

Original languageEnglish (US)
Pages (from-to)585-594
Number of pages10
JournalBiochemical Journal
Volume432
Issue number3
DOIs
StatePublished - Dec 15 2010

Keywords

  • Aging
  • Free radical
  • Hormesis
  • Protein degradation
  • Protein oxidation
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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