ABSTRACT

Ubiquitin modification of a variety of cellular proteins plays a major role in numerous basic cellular processes. Among these are regulation of cell cycle and division, differentiation and development, involvement in the cellular 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 and biogenesis of organelles. The mechanisms that underlie these complex processes are poorly understood and many of the target proteins have yet to be identified. In most cases, modification of the protein substrate by ubiquitin targets it for degradation by the 26S proteasome complex. In some cases however, modification leads to targeting of the protein for degradation in the lysosome or the vacuole. Nonproteolytic functions of ubiquitination have been proposed but never established firmly. The list of cellular proteins that are targeted by the ubiquitin system is growing exponentially. Among them are cell cycle regulators such as mitotic and G 1 cyclins, and cyclin-dependent kinases and their inhibitors. Tumor suppressors such as p53> transcriptional activators and their inhibitors, fos, myc,

NF-κΒ and iKba, for example, cell surface receptors such as the growth hormone receptor and the T cell receptor, and endoplasmic reticulum (ER) proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR), are also targeted by the ubiquitin system. Abnormal and otherwise denatured/ misfolded proteins are recognized specifically and removed efficiently by the system. Degradation of a protein via the ubiquitinproteasome pathway involves two discrete and successive steps:

1. covalent attachment of multiple ubi­ qu itin m olecules to the protein substrate, and

2. degradation of the tagged protein by the 26S proteasome, or in certain cases, by the lysosomes/vacuole (for selected recent reviews on the ubiquitin system, see refs. 1-18).