The role of the proteasome in cellular protein degradation

Abstract

Eukaryotic cells contain a major intracellular proteolytic activity known as the proteasome. The proteasome is a strongly conserved cylindrical structure of high molecular weight (650 kDa, -20 S) and desmonstrates multiple endopeptidase activities. The general structural, biochemical and genetic features of the proteasonie are conserved from archaebacteria through yeast to humans. This structure fulfills an essential role by functioning as the proteolytic core of a 26 S multienzyme complex responsible for the energydependent degradation of ubiquitinated proteins. The bulk of intracellular proteolysis appears to be through the ubiquitin-dependent pathway. Incorporation of the proteasome into the 26 S niultienzyme complex appears to confer both a specificity for ubiquitinated proteins as well as a nieans to tightly regulate proteolytic activity. Thus, one function of the proteasome is required for the degradation of either abnormal or certain regulatory proteins by the ubiquitin pathway. Proteasoine subunits appear to be encoded by a related gene family as defined by extensive sequence similarities. The gene products are confined to either of two general classes: a-type which appear to be structural and 8-type which may be catalytic. Genes encoding at least two proteasome subunits map to the Ma-jor Histocompatibility Complex. Accurnulating evidence points to the proteasome (or a specialized form) participatirig in the cytosolic degradation of these viral proteins upon cellular infection. Through a previously unforseen mechanisin. it appears that the products from the digestion of the viral proteins may be rescued from further digestion to amino acids and shuttled from the cytoplasm through the endoplasniic reticulum to the cell surface where they serve as antigenic peptides for recognition by the immune system. The proteasome may have been recruited by the immune system to serve as the cytosolic activity responsible for generating these antigenic peptides. The proteasome may function in the ubiquitindependent degradation of not only certain self-proteins but may fulfill a second essential role in the degradation of proteins originating from viral infection