We have previously demonstrated that
proteasome serves as a central regulator of
inflammation and macrophage function. Until recently, proteasomes have generally been considered to play a relatively passive role in the regulation of cellular activity, i.e., any ubiquitinated
protein was considered to be in discriminatively targeted for degradation by the
proteasome. We have demonstrated, however, by using specific
proteasome protease inhibitors and knockout mice lacking specific components of immunoproteasomes, that proteasomes (containing X, Y, and
Z protease subunits) and immunoproteasomes (containing LMP7, LMP2, and LMP10
protease subunits) have well-defined functions in
cytokine induction and
inflammation based on their individual
protease activities. We have also shown that LPS-TLR mediated signaling in the murine RAW 264.7 macrophage cell line results in the replacement of macrophage immunoproteasomal subunits. Such modifications serve as pivotal regulators of LPS-induced
inflammation. Our findings support the relatively novel concept that defects in structure/function of
proteasome protease subunits caused by
genetic disorders, aging, diet, or drugs may well have the potential to contribute to modulation of
proteasome activity. Of particular relevance, we have identified
quercetin and
resveratrol, significant constituents present in berries and in red wine respectively, as two novel
proteasome inhibitors that have been previously implicated as disease-modifying natural products. We posit that natural
proteasome inhibitors/activators can potentially be used as therapeutic response modifiers to prevent/treat diseases through pathways involving the
ubiquitin-
proteasome pathway (UP-pathway), which likely functions as a master regulator involved in control of overall inflammatory responses. This article is part of a Special Issue entitled:
Ubiquitin Drug Discovery and Diagnostics.