The ubiquitin–proteasome pathway: on protein death and cell life

The discovery of the ubiquitin pathway and its many substrates and functions has revolutionized our concept of intracellular protein degradation. From an unregulated, non‐specific terminal scavenger process, it has become clear that proteolysis of cellular proteins is a highly complex, temporally controlled and tightly regulated process which plays important roles in a broad array of basic cellular processes. It is carried out by a complex cascade of enzymes and displays a high degree of specificity towards its numerous substrates. Among these are cell cycle and growth regulators, components of signal transduction pathways, enzymes of house keeping and cell‐specific metabolic pathways, and mutated or post‐translationally damaged proteins. The system is also involved in processing major histocompatibility complex (MHC) class I antigens. For many years it has been thought that activity of the system is limited to the cytosol and probably to the nucleus. However, recent experimental evidence has demonstrated that membrane‐anchored and even secretory pathway‐compartmentalized proteins are also targeted by the system. These proteins must be first translocated in a retrograde manner into the cytosol, as components of the pathway have not been identified in the endoplasmic reticulum (ER) lumen. With the multiple cellular targets, it is not surprising that the system is involved in the regulation of many basic cellular processes such as cell cycle and division, differentiation and development, the response to stress and extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels and the secretory pathway, DNA repair, regulation of the immune and inflammatory responses, biogenesis of organelles and apoptosis. One would also predict that aberrations in such a complex system may be implicated in the pathogenesis of many diseases, both inherited and acquired. Recent evidence shows that this is indeed the case. Degradation of a protein by the ubiquitin system involves two distinct …

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