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Proteasome Activator 28γ: Impact on Survival Signaling and Apoptosis

This chapter aims to explain the functional impact of the proteasome activator (PA)28 γ protein in cellular survival. The mechanistic complexity of this proteasome activator, encoded by the PSME3 gene and overexpressed in tumors in correlation with the degree of severity, is attracting growing attention. Taking anti-apoptotic properties of PA28 γ into account, a simple view might explain therapy resistance of tumors by the presence of high concentrations of this proteasome regulator. A more sophisticated approach would con-sider functional parameters such as subcellular distribution, competition with other proteasome regulators, and factors affecting heptamer assembly, proteasome binding, and activation. Recently, PA28 γ has been attributed as a proteasomal recognin, particularly for intrinsically unstructured proteins (IUPs), targeted by ubiquitin-independent proteasomal protein (UIPP) degradation. Other reports demonstrated inhibitory or stimulatory effects of PA28 γ on turnover of substrates of the ubiquitin- and ATP-dependent proteasome system (UPS). Since the understanding of functional implications of PA28 γ on diverse signaling processes has grown exponentially and the orchestration of proteolytic systems within apoptosis is fairly complex, this article summarizes the recent develop-ments in PA28 γ biology with emphasis on cell survival signaling pathways such as DNA repair and apoptosis. are connected by cross talk: 11S and 19S regulators compete for binding to the 20S core protease. Increased assembly of PA28 γ complexes is supposed to reduce the relative amount of 30S proteasomes. In cells overexpressing PA28 γ , certain proteasomal substrates of PA28 γ -20S proteasomes may be recognized by increased turnover, while others may accumulate due to UPS inhibition. The second mode of cross talk takes place, if UIPP degrades E3 enzymes or components required for their activation. As the third mode, PA28 γ might increase PPI between E3s (Mdm2) and their substrates (S1, p53), thereby increasing UPS-dependent substrate turnover.