Ubiquitin/Proteasome System

Ubiquitination

Ubiquitin (Ub) is a polypeptide, 76 amino acids in length, which acts as a molecular label within the UPS. Each Ub polypeptide has seven lysine residues; these are involved in linking multiple Ub polypeptides together to form a polyubiquitin chain. The pattern and distribution of ubiquitination determines the final fate of a protein. For example, monoubiquitination has been linked to endocytosis, protein sorting, nuclear export of proteins, DNA repair and transcription regulation, whilst polyubiquitination signals protein degradation, DNA repair, kinase activation and transcription factor activation.

The process by which proteins are ubiquitinated comprises three main steps:

1. Activation of Ub at its C-terminus by an E1 ubiquitin-activating enzyme
2. Conjugation of Ub to an E2 ubiquitin-conjugating enzyme
3. Transfer of Ub to the substrate protein by an E3 ubiquitin ligase

Protein targets of the UPS include regulators of cell cycle and apoptosis, transcription factors involved in the regulation of cell division, growth, differentiation, signal transduction and response to stress, and therefore the UPS is linked to a multitude of cellular processes. As an example, the UPS components MDM2 and Cullin 3, both E3 ligases, are key regulators of the DNA damage response and the Nrf2 pathway respectively, preventing the inappropriate activation of cellular stress responses.

Dysregulation of the UPS has been linked to a wide variety of diseases, including neurological disorders, cancer and atherosclerosis. Its function is of particular interest in protein-misfolding disorders such as Parkinson's disease and Huntington's disease, where aberrant UPS activity is thought to contribute to the intracellular accumulation of toxic proteins.

Ubiquitin-independent Proteasomal Degradation

Though ubiquitination is one of the main mechanisms for initiating proteasomal degradation of a target protein, emerging evidence suggests that proteins may also be degraded via ubiquitin-independent mechanisms. An example of this is the ubiquitin-independent degradation of topoisomerase IIβ following its persistent interference with RNA polymerase II activity.