G. Fenteany, S. Schreiber
Apr 10, 1998
Citations
5
Influential Citations
414
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Journal
The Journal of Biological Chemistry
Abstract
Lactacystin, a microbial natural product that inhibits cell proliferation and induces neurite outgrowth in a murine neuroblastoma cell line, has become a widely used reagent in functional studies of the proteasome, a high molecular weight, multicatalytic protease complex responsible for most non-lysosomal intracellular protein degradation. The proteasome is composed of a 20 S catalytic core and additional subunits that are thought to be involved in the recognition and unfolding of ubiquitinated proteins; the composite structure has a sedimentation coefficient of 26 S. Lactacystin binds certain catalytic subunits of the 20 S proteasome and inhibits the three best characterized peptidase activities of the proteasome, two irreversibly and all at different rates (1). At least one of these catalytic subunits is modified by lactacystin on the side chain hydroxyl of the amino-terminal threonine (1), which appears to function as the catalytic nucleophile in the proteolytic mechanism. Lactacystin also inhibits peptide hydrolysis by the larger 26 S complex and inhibits ubiquitin/proteasome-mediated degradation of short and long lived proteins in the cell (2). This small molecule is currently the only compound known that inhibits the proteasome specifically without inhibiting any other protease yet tested in vitro (1, 3); also it does not inhibit lysosomal protein degradation in the cell (2). This is in contrast to other commonly used proteasome inhibitors, such as peptide aldehydes and 3,4-dichloroisocoumarin, which inhibit a wide range of proteases. Lactacystin has been used to implicate proteolysis by the proteasome in a number of fundamental processes from cellular differentiation and apoptosis to the degradation of proteins normally residing in the endoplasmic reticulum. In this review, the putative mechanism of action and some applications of lactacystin are discussed, as well as recent findings on proteasome function.