Redox control of protein degradation

It was already known that protein turnover involves multiple pathways, but the role of redox regulation remained unclear. No prior work had resolved how redox-responsive and redox-unresponsive proteolysis coexist. This uncertainty drove the need to synthesize findings on redox control of proteolysis. The literature suggests that glucose metabolism provides energy for redox-responsive degradation. Some proteolytic systems function independently of redox status, creating a gap in understanding their coordination. Prior research has shown that proteases are modulated by sulfhydryl groups and reactive oxygen species. However, the extent of redox influence on various proteolytic systems was not fully established. This review aimed to clarify how redox-responsive and redox-unresponsive mechanisms operate together.

The aim of this review was to synthesize evidence on how redox-responsive and redox-unresponsive proteolytic systems function in cells. The specific problem addressed is the apparent duality in proteolysis regulation. The motivation stems from the need to understand how glucose-derived energy and redox status influence protein degradation. The review sought to clarify the mechanisms by which proteases are modulated by redox changes. It also aimed to explore the role of sulfhydryl proteases in mammalian muscle. The authors wanted to determine whether redox-responsive proteolysis is a coordinated regulatory system. They examined whether redox control affects lysosomal and Golgi-endoplasmic reticulum degradation. The review also sought to identify the extent of redox influence on proteolytic pathways.

The researchers conducted a literature review to compile evidence on redox-responsive proteolysis. They analyzed studies on proteases, inhibitors, and redox-sensitive systems. The review included data on sulfhydryl proteases and their regulation by redox status. They examined the role of thioredoxins and glutaredoxins in reductive activation. The authors considered how metal ions and reactive oxygen species affect proteolytic activity. They evaluated the impact of glucose supply on diamide- and dehydroascorbic acid-induced proteolysis inhibition. The review incorporated findings on lysosomal and Golgi-endoplasmic reticulum degradation. The synthesis of evidence focused on the balance between oxidative inactivation and reductive activation.

The strongest finding is that more than half of total cell proteolysis is redox-responsive. Redox-responsive proteolysis includes Golgi-endoplasmic reticulum and lysosomal degradation. Sulfhydryl proteases are modulated by mixed disulfide formation and reactive oxygen species. Thioredoxins and glutaredoxins are major reductive activators of proteolytic systems. Diamide and dehydroascorbic acid inhibit proteolysis, especially when glucose is available. The inhibition is reversible and depends on the reductive energy supply-demand balance. Redox-responsive proteolysis does not cause ATP depletion, nor is ATP depletion linked to it. The review suggests that redox control coordinates distinct proteolytic processes under certain conditions.

The authors propose that redox-responsive proteolysis is a major component of protein turnover in mammalian cells. They suggest that the machinery of protein degradation evolved with dependencies on the cell redox network. The balance between oxidative inactivation and reductive activation determines proteolytic activity. The review highlights that sulfhydryl proteases are central to redox-responsive degradation. The findings suggest that proteolysis is reversibly modulated by experimental interventions affecting redox status. The authors note that redox-responsive proteolysis is not limited to muscle cells but occurs in various species. They conclude that redox control may coordinate distinct proteolytic pathways under some intracellular conditions. The review emphasizes the need for further studies to clarify the mechanisms of redox-dependent proteolysis.