Differential roles of proteasome and immunoproteasome regulators Pa28αβ, Pa28γ and Pa200 in the degradation of oxidized proteins

The response and functions of proteasome regulators Pa28 alpha beta (or 11S), Pa28 gamma and Pa200 in oxidative-stress adaptation (also called hormesis) was studied in murine embryonic fibroblasts (MEFs), using a well-characterized model of cellular adaptation to low concentrations (1.0-10.0 uM) of hydrogen peroxide (H2O2), which alter gene expression profiles, increasing resistance to higher levels of oxidative-stress. Pa28 alpha beta bound to 20S proteasomes immediately upon H2O2-treatment, whereas 26S proteasomes were disassembled at the same time. Over the next 24 h, the levels of Pa28 alpha beta,Pa28 gamma and Pa200 proteasome regulators increased during H2O2-adaptation, whereas the 19S regulator was unchanged. Purified Pa28 alpha beta, and to a lesser extent Pa28 gamma , significantly increased the ability of purified 20S proteasome to selectively degrade oxidized proteins: Pa28 alpha beta also increased the capacity of purified immunoproteasome to selectively degrade oxidized proteins but Pa28 gamma did not. Pa200 regulator actually decreased 20S proteasome and immunoproteasome's ability to degrade oxidized proteins but Pa200 and poly-ADP ribose polymerase may cooperate in enabling initiation of DNA repair. Our results indicate that cytoplasmic Pa28 alpha beta and nuclear Pa28 gamma may both be important regulators of proteasome's ability to degrade oxidatively-damaged proteins, and induced-expression of both 20S proteasome and immunoproteasome, and their Pa28 alpha beta and Pa28 gamma regulators are important for oxidative-stress adaptation. (C) 2012 Elsevier Inc. All rights reserved.