The UPS targets cyclins and cyclin-dependent kinase inhibitors-a class of proteins that control the cell cycle-to coordinate cell growth and division. In addition to modulating protein expression, the UPS mediates cell growth through direct coordination of interphase progression by targeting cell cycle regulators for degradation. The UPS regulates protein expression levels through protein turnover, governing protein synthesis and degradation based on cellular needs. The orderly degradation and recycling of cellular components acts as a quality control system, removing unnecessary or dysfunctional proteins. This tightly regulated, ubiquitin-mediated protein degradation system plays crucial roles in the pathways for cell survival (e.g., autophagy) and cell death (e.g., apoptosis). The proteasome binds the ubiquitinated substrate and unfolds the protein, allowing deubiquitinating enzymes to remove the ubiquitin molecules, after which the protein is transferred into the central core of the proteasome for proteolysis (Figure 1). Polyubiquitinated proteins are recognized and degraded by a large, multi-subunit protease complex known as the proteasome. This process of ubiquitination occurs through the sequential action of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). The UPS selectively targets the degradation of intracellular proteins tagged with ubiquitin (Ub). The dynamic regulation and maintenance of the proteome requires precise control of the synthesis, folding, trafficking, and degradation of proteins. In this article, we will discuss the different pathway mechanisms, the cellular functions each pathway mediates, and which assays can be used to evaluate protein degradation. Given the UPS and lysosomal proteolysis pathway act concurrently, it is not surprising that they share components of their molecular machineries and directly influence each other’s activity.

As a result, dysregulation of these two pathways is implicated in an array of diseases, including multiple cancers, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and cystic fibrosis. Maintaining cellular homeostasis and physiological functions through moderation of proteins is dependent on both the UPS and the lysosomal degradation pathway. In addition, protein quality control is mediated by the UPS, contributing to cellular protein turnover by degrading misfolded, dysfunctional, or otherwise aberrant proteins. The two major protein degradation pathways-the UPS and the lysosomal proteolysis pathway-regulate many cellular processes, including cell cycle, cell signaling, stress response, apoptosis, autophagy, protein expression, and DNA transcription.

Protein turnover definition