Enhancement of proteasome function by PA28α overexpression protects against oxidative stress

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 PA28 alpha overexpression (PA28 alpha OE) stabilized PA28 beta, increased 11S proteasomes, and enhanced the degradation of a previously validated proteasome surrogate substrate (GFPu) in cultured neonatal rat cardiomyocytes. PA28 alpha OE significantly attenuated H2O2-induced increases in the protein carbonyls and markedly suppressed apoptosis in cultured cardiomyocytes under basal conditions or when stressed by H2O2. We conclude that PA28 alpha OE 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.-Li, J., Powell, S. R., Wang, X. Enhancement of proteasome function by PA28 alpha overexpression protects against oxidative stress. FASEB J. 25, 883-893 (2011). www.fasebj.org