Proteasomal Defense of Oxidative Protein Modifications

Abstract

The proteasome has an important role in the degradation of normal, damaged, mutant, or misfolded proteins. This includes the degradation of normal and regulatory proteins in the cellular metabolism and additionally the removal of damaged proteins as a stress response. The two well-described proteasome regulators, the 11S and the 19S regulators, forming together with the 20S 'core' proteasome various forms of the proteasome, including the ATP-stimulated 26S proteasome. As a result of aerobic metabolism, reactive oxygen species (ROS) are constantly generated during the lifetime of biological organisms. Consequently a permanent generation of oxidative damage takes place. This includes the formation of oxidatively modified proteins. These oxidized protein derivatives tend to aggregate, and accumulation of these aggregates may lead to cell death. To prevent this, such oxidatively modified proteins are selectively recognized and either repaired or degraded by the proteasome. The current knowledge of the repair systems and the degradation mechanism is reviewed here. The possible interactions between the ubiquitin-proteasome-system, the chaperone system, the protein repair mechanisms, and other antioxidative defense strategies are highlighted.

The effect of temperature adaptation on the ubiquitin-proteasome pathway in notothenioid fishes

“…It is possible that the antioxidant defense mechanisms in place are not sufficient to fully protect cellular protein integrity and the Ub-proteasome system has an important role in ensuring oxidatively damaged proteins are quickly degraded. The Ub-proteasome pathway has a key role in the degradation of oxidized proteins (Grune et al, 2003;Poppek and Grune, 2006). Lamarre and colleagues (2009) suggest that wolffish maintain high 20S proteasome activity following cold acclimation as a mechanism to remove proteins damaged by oxidative stress.…”

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

“…In addition to protein degradation during axonal degeneration, the proteasome has also been suggested to function in the regulation of signaling pathways that control axonal survival and degeneration under stress (MacInnis and Campenot, 2005). The potential importance of the UPS system in oxidative mechanisms of neurodegeneration appears to be associated with its involvement in the regulated degradation of oxidatively modified proteins (Poppek and Grune, 2006). Protein oxidation and generation of associated cytotoxic compounds are evident during glaucomatous neurodegeneration as summarized in sections 5.1 and 6.2.…”

“…By inhibiting the proteasome function, these aggregated, cross-linked, and oxidized protein products of oxidative stress cause a vicious cycle of progressively worsening accumulation of cytotoxic protein oxidation products (Davies, 2001;Poppek and Grune, 2006). Accumulation of the proteolysis-resistant ineffective protein aggregates leads to a loss in specific protein function, depletion of the cellular redox balance, and ultimately cell death (Berlett and Stadtman, 1997;Dean et al, 1997).…”

Proteasome modulates mitochondrial function during cellular senescence

“…Proteasome is mainly associated with the elimination of abnormal, oxidized and misfolded proteins [10,11]. Recently, it has been suggested that it may be part of cellular defense mechanism by controlling protein oxidative damage [12], [13], [14,15]. Proteasome function is also necessary for the normal turnover of short-lived proteins involved in cell cycle progression [16], gene expression [17], apoptosis [18,19], antigen presentation [20] and signal transduction [7,21,22].…”