Redox Control of the Ubiquitin-Proteasome System: From Molecular Mechanisms to Functional Significance

In their natural environments, cells are regularly exposed to oxidizing conditions that may lead to protein misfolding. If such misfolded proteins are allowed to linger, they may form insoluble aggregates and pose a serious threat to the cell. Accumulation of misfolded, oxidatively damaged proteins is characteristic of many diseases and during aging. To counter the adverse effects of oxidative stress, cells can initiate an antioxidative response in an attempt to repair the damage, or rapidly channel the damaged proteins for degradation by the ubiquitin-proteasome system (UPS). Recent studies have shown that elements of the oxidative stress response and the UPS are linked on many levels. To manage the extra burden of misfolded proteins, the UPS is induced by oxidative stress, and special proteasome subtypes protect cells against oxidative damage. In addition, the proteasome is directly associated with a thioredoxin and other cofactors that may adjust the particle's response during an oxidative challenge. Here, we give an overview of the UPS and a detailed description of the degradation of oxidized proteins and of the crosstalk between oxidative stress and protein degradation in health and disease. Antioxid. Redox Signal. 15, 2265–2299. I. Introduction II. The Ubiquitin System A. E3 ubiquitin-protein ligases B. Deubiquitylation III. The Proteasome A. The 20S proteasome B. The 19S regulatory complex C. Other proteasome activators D. The immunoproteasome IV. Degradation of Misfolded Secretory Proteins V. Protein Aggregation and Aggresomes VI. The role of the proteasome in degradation of oxidized proteins A. The role of the 20S proteasome in degradation of oxidized proteins B. The role of the 26S proteasome in degradation of oxidized proteins VII. The Immunoproteasome Protects Cells from Inflammation-Induced Oxidative Stress VIII. Regulating Proteasome Expression IX. Oxidative Stress and the Ubiquitylation System X. Oxidation-Induced Changes in the 26S Proteasome XI. Proteasome-Associated Oxidoreductases XII. Arsenite Regulation of Proteasome Composition XIII. Proteasome Function in Mitochondrial Maintenance XIV. The UPS and Aging XV. Proteasome Inhibitors and Cancer XVI. The UPS in Neurodegenerative Diseases XVII. Conclusions