Intracellular Protein Degradation

A Pervasive Regulatory Mechanism in Health and Disease

The regulation of most cellular functions centers on control of levels and activities of proteins that carry out those functions. Regulation of protein content and activity is determined by the relative contributions of three general processes: protein production (gene expression/protein synthesis), protein regulation (allostery/posttranslation modifications/protein-protein interactions), and protein degradation.

Historically, protein degradation was the least appreciated and least understood part of this trio. However, it is now clear that protein degradation regulates nearly every important aspect of cell function including cell cycle progression, transcription, overall growth and atrophy, intracellular signaling, metabolite production and flux, protein quality control, apoptosis, inflammation, and immune function.

Because of the widespread role of protein degradation for normal cellular function, it is not surprising that dysfunctional protein degradation is intimately involved in many diseases including cancers, myopathies, and neurodegenerative, metabolic, and autoimmune disorders. Accordingly, many elements of the molecular mechanisms of protein degradation are therapeutic targets of these diseases. In fact, drugs that alter protein degradation pathways are currently used to treat diseases and many more are in development or in various stages of clinical trials.

Despite this impressive progress, many basic features of the molecular and cellular mechanisms and regulation of protein degradation remain poorly understood. Ongoing and future research is required for a comprehensive and deeper understanding of normal mechanisms and regulation of protein degradation and how to exploit this knowledge the creation of therapeutics to treat serious human diseases.