The cellular life relies on the activity of proteins. In each cell, the abundance and thereby the activity of every protein is tightly controlled. It is the result of a balance between synthesis from the genome and degradation by proteolysis.

• The degradation of proteins by the ubiquitin-proteasome pathway

The ubiquitin-proteasome pathway is the major process responsible for the degradation of proteins in all human cells.

It is a highly specific, temporally controlled and tightly regulated process that plays a major role in nearly every aspect of cellular biochemistry. Protein degradation by the ubiquitin-proteasome pathway has been demonstrated to contribute prominently to the regulation of DNA repair, gene expression, apoptosis, cell cycle and the immune response.

• Ubiquitin and human diseases

Given the high number of cellular pathways that are controlled by proteins degradation, it is not surprising that alterations of the ubiquitin-proteasome pathway underlie the pathogenesis of many inherited as well as acquired human diseases, including :

• cancer (colon carcinoma, lymphoma, …)
• inflammatory diseases
• neurodegenerative diseases
  (Parkinson, Alzheimer, Huntington, …)

Likewise, the ubiquitin-proteasome pathway has been shown to be manipulated by many pathogens, including viruses, to circumvent cell defences.

• Ubiquitin ligases : arbiters of protein degradation

The degradation of proteins by the ubiquitin-proteasome pathway involves two successive steps. First, the proteins to be degraded are selected by specific enzymes called ubiquitin ligases. The ubiquitin ligases tag the selected proteins by attaching them a specific poly-ubiquitin chain. Then, after they have been tagged, these ubiquitinated proteins are recognized and degraded by the proteasome 26S. The proteasome is a large complex made up of many proteases that degrade ubiquitinated proteins to multiple small inactive pieces.

The ubiquitin ligases are thus the genuine arbiters of the proteins’ survival because they are responsible for both the efficiency and the selectivity of their degradation by the ubiquitin-proteasome pathway. Recent estimates indicate that the human genome is coding for at least 150 ubiquitin ligases belonging to several structural groups.

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