title: Enhancement of proteasome function by PA28&alpha; overexpression protects against oxidative stress.
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(2)O(2)-induced increases in the protein carbonyls and markedly suppressed apoptosis in cultured cardiomyocytes under basal conditions or when stressed by H(2)O(2). 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.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 East Clark St., Lee Medical Bldg., Vermillion, SD 57069, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Saul R
authors.initials: SR
authors.lastname: Powell
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D018384:Oxidative Stress / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011817:Rabbits; D051381:Rats
chemical_list: D000906:Antibodies; D018797:Cell Cycle Proteins; D011506:Proteins; C490050:Psme1 protein, rat; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse; C486214:Psme2 protein, mouse; C119011:26S proteasome non-ATPase regulatory subunit 13