Protein Degradation and the Pathologic Basis of Disease

Abstract

The abundance of any protein is determined by the balance of protein synthesis and protein degradation. Regulated protein degradation has emerged as a powerful means of precisely controlling individual protein abundance within cells and is largely mediated by the ubiquitin-proteasome system (UPS). By controlling the levels of key regulatory proteins, the UPS contributes to nearly every aspect of cellular function. The UPS also functions in protein quality control, rapidly identifying and destroying misfolded or otherwise aberrant proteins that may be toxic to cells. Increasingly, we understand that dysregulation of protein degradation pathways is critical for many human diseases. Conversely, the versatility and scope of the UPS provides opportunities for therapeutic intervention. In this review, we will discuss the basic mechanisms of protein degradation by the UPS. We will then consider some paradigms of human disease related to protein degradation using selected examples. Finally, we will highlight several established and emerging therapeutic strategies based on altering pathways of protein degradation.

Figure 1

Overview of the ubiquitin-proteasome system for protein degradation. Many proteins misfold either during or immediately after protein synthesis (upper pathway). These proteins (red) are recognized by a series of ubiquitinating enzymes, known as E1, E2, and E3, that covalently attach the small protein ubiquitin (green) to the misfolded protein. This ubiquitin signal allows the protein to be recognized by the proteasome. The proteasome binds the ubiquitinated substrate, unfolds it, removes its ubiquitin molecules, and injects the protein into the central core of the proteasome, where the protein is degraded into small polypeptides. Properly folded proteins are also subject to degradation (lower pathway). In these cases, by controlling the abundance of key regulatory proteins, the ubiquitin-proteasome system contributes to nearly every aspect of cell biology. Some well-characterized examples are listed. Moreover, any properly folded protein can be converted into a misfolded protein at any time because of exposure to any of the numerous stressors that cause protein misfolding, only a few of which are listed.

Figure 2

Lewy bodies associated with Parkinson disease. A hematoxylin and eosin–stained section from the substantia nigra is shown. Two Lewy bodies are present within the cytoplasm of a dopaminergic neuron present at the center of the image. Original magnification, ×400.

Figure 3

Simple schematic for therapeutic intervention based on protein degradation. Left panel: Many diseases are driven by the accumulation of one or more proteins. These may be key regulatory proteins or toxic misfolded proteins. Targeted degradation of these proteins may lead to disease amelioration (red arrow). Right panel: Other diseases may be caused by a relative lack of functional protein. This may be due to partial misfolding and degradation, or otherwise excessive degradation of key mediators. In these cases, interventions to increase the yield of properly folded functional protein may be effective (red arrow).