Deubiquitinating enzymes: their roles in development, differentiation, and disease

The ubiquitin-mediated proteolysis pathway has come a long way in the past decade. At first thought to be an unglamorous garbage dump for damaged proteins, the ubiquitin pathway has been shown to regulate virtually everything that occurs in the cell. Deubiquitinating enzymes, which cleave ubiquitin-protein bonds, are the largest group of enzymes in the pathway, yet they are the least well understood. Deubiquitinating enzymes have two kinds of functions: housekeeping and regulatory. The housekeeping enzymes facilitate the proteolytic pathway. By contrast, the regulatory enzymes control the ubiquitination of specific protein substrates; their relationship to ubiquitination is analgous to that of phosphatases with respect to phosphorylation. Here, I review the current state of knowledge of the deubiquitinating enzymes. I focus particularly on the known regulatory enzymes, and also on the housekeeping enzymes that are implicated in development of disease.