Regulating Proteasome Activity

Strictly controlled degradation of the proteome is a key factor in maintaining cellular homeostasis and allows a rapid and effective response to a variety of different stress challenges. The central element of the regulatory degradative network that integrates different stimuli and signals is the proteasome, a macromolecular machine designed to selectively remove specific proteins according to the variable needs of the cell. Not surprisingly, given the extreme complexity and interdependence of the pathways involved, the proteolytic system has evolved with a modular organization based on a central hydrolytic element, the 20S proteasome, to which alternative regulatory modules can associate to fine-tune its activity. Perturbation of this delicate network is involved in the onset of various pathological conditions (e.g., cancer, neurodegenerative diseases, inflammatory and autoimmune disorders, infections), and in recent years strategies for modulating this proteolytic pathway (mainly through molecules that inhibit key enzymatic activities of this degradative system) have been shown to be extremely useful for both research and therapeutic purposes.