Targeting Proteasome Worsens Atherosclerosis

Abstract

See related article, pages 865–874 The ubiquitin–proteasome system is the major pathway (up to 80% to 90%) of nonlysosomal degradation of intracellular and oxidized proteins1–3 (Figure). For a protein to be recognized by the proteasome, a small peptide (ubiquitin) must first be attached to the target protein. The process of ubiquitination which transfers polyubiquitin chains to target proteins requires various enzymes such as ubiquitin-activating enzyme (E1), ubiquitin carrier protein (E2), and ubiquitin-protein lipase (E3). The ubiquitinated substrate is rapidly hydrolyzed by the 26S proteasome, an ATP-dependent multiprotein complex containing the proteolytically active 20S proteasome that is capped by 1 or 2 19S regulatory complexes.4 The 20S proteasome has 3 distinct proteolytic activities harbored by β subunits which consist of caspase-like (β1 subunit), trypsin-like (β2 subunit), and chymotrypsin-like (β5 subunit) activities.5 The primary inhibitory effect of overall proteasome proteolytic function is mediated through chymotrypsin-like function of the 20S proteasome.5 Indeed, most of synthetic and natural inhibitors of the proteasome such as MLN-273 and PS-341 act predominantly on the chymotrypsin-like activity.1 In particular, PS-341 (bortezomib [Velcade]) was approved for the treatment of therapy-refractory multiple myeloma in 2003.6 Figure. Role of ubiquitin-proteasome system in atherosclerosis. The protein substrates such as cell mediators involved in atherosclerosis and oxidized protein are first conjugated to multiple molecules of ubiquitin in a reaction involving ubiquitin-activating enzyme (E1), ubiquitin carrier protein (E2), and ubiquitin-protein ligase (E3). The ubiquitinated substrate is rapidly hydrolyzed by the 26S proteasome containing the core 20S proteasome (formed by 2 outer α subunits and 2 inner …