Ubiquitin-Proteasome System for Controlling Cellular Protein Levels

Cells contain many different kinds of proteins, each fulfilling structural, functional, or regulatory roles. Monitoring the state of all these proteins, as well as continuously adjusting their levels to suit demands is paramount to survival. The presence of damaged or mutated proteins, as well as altered levels of normal proteins could cause pathological conditions and even cell death. To exercise such quality control, cells are continuously spending energy both to synthesize new proteins, and to simultaneously degrade them, even though many may still be functional. An important characteristic of regulatory degradation is that it is specific; only the correct proteins are removed in a time-coordinated manner. Such extraordinary specificity is achieved by a modular system that identifies the proteins to be degraded, marks them by covalently attaching ubiquitin to an amino residue, and finally proteolyses the substrate by the 26S proteasome. Recognition of target proteins is carried out by a specific ubiquitin-protein ligase, called an E3. This protein recognizes the substrate and usually directs a ubiquitin-conjugating enzyme, an E2, to attach ubiquitin, a small 76 amino acid protein, onto the substrate. Ubiquitin molecules are often added to one another as well as to the substrate, resulting in chains of ubiquitin extending from the protein targeted for degradation. These polyubiquitin conjugates are then shuttled to the 26S proteasome, a large proteolytic complex, where they are degraded. Interestingly, ubiquitination is a reversible process, with deubiquitinating enzymes able to remove ubiquitin from the target before it can be recognized by the proteasome. Hence, transfer of the polyubiquitinated conjugate to the proteasome must happen swiftly or be shielded from these enzymes. The balance of these processes allows the ubiquitin-proteasome system to control the cellular levels and half lives of thousands of proteins making it a key player in basic biological pathways such as cell division, differentiation, signal transduction, trafficking, and quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many diseases, certain malignancies, neurodegenerative disorders, inflammation, and immune response. Understanding the underlying mechanisms involved is important for the development of novel, mechanism-based drugs. Keywords: Deubiquitination; ER-associated Degradation (ERAD); Proteasome (a.k.a. 26S proteasome); Proteolysis or Protein Degradation; Ubiquitin; Ubiquitinating Enzymes; Ubiquitination; Ubiquitin-like Proteins