Enhancement of proteasome function by PA28α overexpression protects against oxidative stress

Jie Li, Saul R. Powell, Xuejun Wang

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

The principal function of the proteasome is targeted degradation of intracellular proteins. Proteasome dysfunction has been observed in experimental cardiomyopathies and implicated in human congestive heart failure. Measures to enhance proteasome proteolytic function are currently lacking but would be beneficial in testing the pathogenic role of proteasome dysfunction and could have significant therapeutic potential. The association of proteasome activator 28 (PA28) with the 20S proteasome may play a role in antigen processing. It is unclear, however, whether the PA28 plays any important role outside of antigen presentation, although up-regulation of PA28 has been observed in certain types of cardiomyopathy. Here, we show that PA28α overexpression (PA28αOE) stabilized PA28β, increased 11S proteasomes, and enhanced the degradation of a previously validated proteasome surrogate substrate (GFPu) in cultured neonatal rat cardiomyocytes. PA28αOE significantly attenuated H 2O2-induced increases in the protein carbonyls and markedly suppressed apoptosis in cultured cardiomyocytes under basal conditions or when stressed by H2O2. We conclude that PA28αOE is sufficient to up-regulate 11S proteasomes, enhance proteasome-mediated removal of misfolded and oxidized proteins, and protect against oxidative stress in cardiomyocytes, providing a highly sought means to increase proteasomal degradation of abnormal cellular proteins.

Original languageEnglish (US)
Pages (from-to)883-893
Number of pages11
JournalFASEB Journal
Volume25
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Apoptosis
  • Cell culture
  • Green fluorescence protein
  • Oxidized proteins
  • Proteasome activator 28

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Enhancement of proteasome function by PA28α overexpression protects against oxidative stress'. Together they form a unique fingerprint.

  • Cite this