The proteasome is a multi-catalytic proteolytic complex, which recognizes and selectively degrades oxidatively damaged and ubiquitinated proteins. One of the hypothesis put forward to explain the accumulation of altered proteins is the decrease of proteasome activity with age. Indeed, accumulation of altered protein can be explained by increased protein alteration, decreased protein degradation or the combination of both. Damage to macromolecules, and in particular protein, implicated in the cellular degeneration that occurs during the aging process, is corroborated by the accumulation of oxidative end-products over time. Oxidized protein build up is commonly seen as a hallmark of cellular aging. Heat-shock protein 90 (Hsp 90) is implicated in both protection against oxidative inactivation and inhibition of the 20S proteasome.
The 26S proteasome is an essential component of the ubiquitin and ATP-dependent proteolytic pathway. It plays a crucial role in the turnover of cytosolic proteins but is not only a “housekeeping” enzyme. In fact, beside eliminating abnormal proteins that are either misfolded or altered, it also participates to the activation of essential functions of the cell. Indeed, the proteasome is implicated in a broad range of cellular pathways such as apoptosis, cell cycle, cell differentiation, DNA repair and degradation of many important rate-limiting enzymes in metabolic pathways. The 20S proteasome catalytic core is a high molecular weight complex of 700 kDa which represents up to 1% of soluble cellular proteins. In the cell, this complex constitutes the main non-lysosomal proteolytic machinery implicated in protein degradation. The proteasome is located in the cytosol and in nucleus and is associated to the reticulum. The αsubunits form the outer rings of the cylinder while the β subunits form the two inner rings and three of the subunits carry the catalytic activities.
Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. The oxidative inactivation of the proteasome is a molecular link between oxidative stress and overexpression of interleukin (IL)-8. The sequence of events in signaling cascade that leads to up-regulation of IL-8 in response to proteasome inactivation includes proteasome inactivation, activation of mitogen-activated protein kinase kinase (MKK)3/MKK6, activation of p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation and increased IL-8 expression.