Ubiquitin Pathway


Ubiquitination is an enzymatic process that involves the covalent attachment of the conserved protein ubiquitin to a substrate. Protein ubiquitination is carried out by the sequential and coordinate actions of three enzymes and can be removed by deubiquitinases. Modification of proteins by addition of ubiquitin exerts both proteolytic‐dependent and proteolytic‐independent functions. Polyubiquitin chains act as a signal for 26S proteasome‐mediated degradation. Ubiquitination plays a central regulatory role in a number of cellular processes such as receptor endocytosis, cell cycle control, transcription, DNA repair, gene silencing and stress response. The ubiquitin proteasome system (UPS) is critical for the proper turnover of both oncoproteins and tumour suppressor molecules. As a result, it is not surprising that aberrations within the UPS often result in a neoplastic phenotype.

Key Concepts

  • Ubiquitination is an ATP‐dependent and reversible process through which ubiquitin is covalently attached to a polypeptide.
  • The topology of the polyubiquitin chains dictates the fate of the modified protein.
  • Deubiquitinating enzymes (DUBs) are proteases that reversely modify proteins by removing ubiquitin.
  • The RING finger type E3 ligases crucially control cell cycle entry and progression.
  • The proteasome is a proteolytic ‘machinery’ that digests proteins into short polypeptides.
  • The ubiquitin proteasome system (UPS) degrades 80–90% of all intracellular proteins.
  • The UPS regulates the timing and extent of protein turnover.

Keywords: ubiquitin; ubiquitination; deubiquitination; protein degradation; proteasome; cell cycle

Figure 1. Ubiquitin (Ub) pathway. DUB denotes a deubiquitinating enzyme. The symbol ‘∼’ denotes a high‐energy thioester bond.
Figure 2. Structural models of the mammalian APC/C and SCF RING finger E3 complexes. The APC/C consists of at least 14 core subunits. The complex recruits substrates (S) via one of the two adaptor proteins, Cdc20 or Cdh1. In addition, APC/C is composed of the RING finger protein APC11, which binds directly to E2, and a cullin‐like subunit APC2. The other APC proteins are regulatory subunits displaying scaffolding, catalytic or substrate recognition functions. The SCF complex consists of RING box protein 1 (Rbx1), which associate with E2 enzymes, Cullin 1 and SKP1. This adaptor protein interacts with one of several F‐box proteins that act as substrate recognition modules.
Figure 3. 26S proteasome. The representation of the 20S proteasome is based on crystal structures. The representation of the 19S complex is loosely based on electron tomographic images.
Figure 4. Simplified examples of the co‐regulation between SCF and APC/C complexes activity during cell cycle progression. APC/CCdh1 activity is restricted in G1 phase where it promotes the degradation of positive regulators of the cell cycle machinery, such as the F‐box protein Skp2. In the G2/M transition, SCFβTrCP promotes the degradation of Wee1, thus activating cdk1. SCFβTrCP also induces the degradation of Emi1, an inhibitor of the APC/C complex (both APC/CCdc20 and APC/CCdh1), thus allowing the execution of cell division and the establishment of the G1 phase of the next cell cycle. Several SCF E3 ligases control the degradation of modulators of Cdks activity (such as cyclin E and cyclin D) throughout the cell cycle (see text for details).


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Further Reading

Bassermann F , Eichner R and Pagano M (2014) The ubiquitin proteasome system implications for cell cycle control and the targeted treatment of cancer. Biochimica et Biophysica Acta 1843 (1): 150–162.

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Peschiaroli, Angelo, Lam, Y Amy, Pickart, Cecile M, Barlev, Nickolai A, Melino, Gerry, and Bernassola, Francesca(May 2017) Ubiquitin Pathway. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000685.pub2]