The ubiquitin-proteasome pathway (UPP) is the principal mechanism for protein catabolism in the mammalian cytosol and nucleus. The highly regulated UPP affects a wide variety of cellular processes and substrates. Defects in the system can result in the pathogenesis of several important human diseases. Degradation of a protein via the ubiquitin-proteasome pathway involves two discrete and successive steps: (1) tagging of the substrate protein by the covalent attachment of multiple ubiquitin molecules (conjugation); and (2) the subsequent degradation of the tagged protein by the 26S proteasome, composed of the catalytic 20S core and the 19S regulator (degradation). This classical function of ubiquitin is associated with housekeeping functions, regulation of protein turnover, and antigen‑peptide generation. More recently, it has become evident that protein modification by ubiquitin also has unconventional (non-degradative) functions such as the regulation of DNA repair and endocytosis. These non-traditional functions are dictated by the number of ubiquitin units attached to proteins (mono versus poly-ubiquitination) and also by the type of ubiquitin chain linkage that is present.

Ubiquitin–Proteasome Pathway References