Oxidative stress-mediated regulation of proteasome complexes

Abstract

Oxidative stress has been implicated in aging and many human diseases, notably neurodegenerative disorders and various cancers. The reactive oxygen species that are generated by aerobic metabolism and environmental stressors can chemically modify proteins and alter their biological functions. Cells possess protein repair pathways to rescue oxidized proteins and restore their functions. If these repair processes fail, oxidized proteins may become cytotoxic. Cell homeostasis and viability are therefore dependent on the removal of oxidatively damaged proteins. Numerous studies have demonstrated that the proteasome plays a pivotal role in the selective recognition and degradation of oxidized proteins. Despite extensive research, oxidative stress-triggered regulation of proteasome complexes remains poorly defined. Better understanding of molecular mechanisms underlying proteasome function in response to oxidative stress will provide a basis for developing new strategies aimed at improving cell viability and recovery as well as attenuating oxidation-induced cytotoxicity associated with aging and disease. Here we highlight recent advances in the understanding of proteasome structure and function during oxidative stress and describe how cells cope with oxidative stress through proteasome-dependent degradation pathways.

Fig. 1.

Cellular Response to Oxidative Stress. Shown here is a flow chart detailing the production of reactive oxygen species (ROS) and the subsequent cellular response resulting in either the return to normal cellular homeostasis or apoptotic/necrotic cell death.

Fig. 2.

Model of oxidative stress-dependent regulation of proteasomes. In the early phase of cellular response to oxidative insult, various changes occur to modulate 26S and 20S proteasome activity in order to promote the degradation of oxidized proteins, and limit the damage of oxidative stress. Initially, under milder stress conditions, 26S proteasomes are activated by mechanisms still unknown. With persistent oxidative insult, or application of acute oxidative stress, proteasomes disassemble into 20S CPs and 19RPs. In yeast, the PIP Ecm29 is required for this disassembly (77). Following dissociation, free 20S proteasomes are activated and oxidized proteins are degraded independently of ATP and ubiquitin. If cells undergo prolonged exposure to oxidative stress (at least 12 h), cells enter the late phase of cellular response to oxidative stress. Though the exact mechanism is unknown, 26S proteasome inhibition ultimately signals the synthesis of new proteasome components and the formation of functional proteasome degradation units. Of note * 20S, i20S, and i26S proteasomes are more effective than standard 26S proteasomes for degrading oxidized proteins.