Redox Control of Protein Degradation

This review summarizes evidence that most of cell protein degradation is maintained by pathways transferring energy from glucose to reduction of enzymic and nonenzymic proteins (redox-responsive). In contrast, a major subcomponent of proteolysis is simultaneously independent of the cell redox network (redox-unresponsive). Thus far, direct and indirect redox-responsive proteolytic effector mechanisms characterized by various investigators include: several classes of proteases, some peptide protease inhibitors, substrate conjugation systems, substrate redox and folding status, cytoskeletal-membrane kinesis, metal homeostasis, and others. The present focus involves redox control of sulfhydryl proteases and proteolytic pathways of mammalian muscle; however, other mechanisms, cell types, and species are also surveyed. The diversity of redox-responsive catabolic mechanisms reveals that the machinery of protein turnover evolved with fundamental dependencies upon the cell redox network, as observed in many species. The net redox status of a reversible proteolytic effector mechanism represents the balance between combined oxidative inactivating influences versus reductive activating influences. Similar to other proteins, redox-responsive proteolytic effectors appear to be oxidized by mixed disulfide formation, nitrosation, reactive oxygen species, and associations or reactions with metal ions and various pro-oxidative metabolites. Systems reducing the proteolytic machinery include major redox enzyme chains, such as thioredoxins or glutaredoxins, and perhaps various reductive metabolites, including glutathione and dihydrolipoic acid. Much of mammalian intracellular protein degradation is reversibly responsive to noninjurious experimental intervention in the reductive energy supply-demand balance. Proteolysis is reversibly inhibited by diamide or dehydroascorbic acid; and such antiproteolytic actions are strongly dependent on the cell glucose supply. However, gross redox-responsive proteolysis is not accompanied by ATP depletion or vice versa. Redox-responsive proteolysis includes Golgi-endoplasmic reticulum degradation, lysosomal degradation, and some amount of extravesicular degradation, all comprising more than half of total cell proteolysis. Speculatively, redox-dependent proteolysis exhibits features expected of a controlling influence coordinating distinct proteolytic processes under some intracellular conditions.