Proteasome activation as a novel antiaging strategy

Summary Homeostasis is a key feature of cellular lifespan. Mainte- nance of cellular homeostasis influences the rate of aging and is determined by several factors, including efficient proteolysis of damaged proteins. Protein degradation is predominately cata- lyzed by the proteasome. Specifically, the proteasome is respon- sible for cell clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short-lived proteins. As proteasome has an impaired function during aging, emphasis has been given recently in identifying ways of its activation. A number of studies have shown that the proteasome can be activated by genetic manipulations as well as by factors that affect its conformation and stability. Impor- tantly the developed proteasome activated cell lines exhibit an extended lifespan. This review article discusses in details the various factors that are involved in proteasome biosynthesis and assembly and how they contribute to its activation. Finally as few natural compounds have been identified having protea- some activation properties, we discuss the advantages of this novel antiaging strategy. 2008 IUBMB IUBMB Life, 60(10): 651-655, 2008 Protein degradation is predominately catalyzed by the protea- some. The proteasome is responsible for cell clearance of abnormal, denatured or in general damaged proteins as well as, for the regulated degradation of short-lived proteins (2, 3). The 20S proteasome, a 700 kDa multisubunit enzyme complex, is a barrel-shape stack of four heptameric rings localized in both cytoplasm and nucleus. The two outer a-subunits rings (a1-7) embrace two central head-to-head oriented rings containing b-subunits (b1-7). The internal chamber that is composed by b-subunits hosts the proteolytic active sites. Three of the b-sub- units, b1, b2, and b5, are responsible for the proteasome hydro- lyzing activities that cleave peptide bonds on the carboxyl site of acidic (peptidylglutamylpeptide hydrolyzing activity, PGPH), basic (trypsin-like activity, T-L), and hydrophobic (chymotryp- sin-like activity, CT-L) amino acids, respectively (3). Capping of each side of 20S particle by 19S regulatory com- plexes gives rise to 26S proteasome that is responsible for the ATP/ubiquitin-dependent protein degradation. The 19S particle is composed of two subcomplexes, namely the lid and the base. The lid covers the base and it is involved in the recognition and ubiquitin chain processing of substrates before their transloca- tion and degradation. The base is consisted of six ATPase subu- nits involved in the unfolding and further translocation of the substrate (4). The target protein is first labeled via covalent attachment of multiple ubiquitin molecules before the degrada- tion by the 26S complex. Three steps are involved in the conju- gation of ubiquitin to the substrate. Ubiquitin is activated by E1, the ubiquitin-activating enzyme, and then transferred by an E2 enzyme, the ubiquitin-carrier protein or ubiquitin-conjugat- ing enzyme, to a member of the ubiquitin-protein ligase family, E3, to which the target protein is specifically bound. This enzyme catalyzes the repeated conjugation of ubiquitin to the substrate prior of the 26S complex-mediated degradation (2). Proteasome has also been implicated in antigen presentation process and immune response, mainly through immunoprotea- somes. In this proteasome type, the constitutively expressed b1, b2, and b5 subunits are substituted during de novo proteasome biosynthesis by b1i, b2i, and b5i subunits respectively. As a result, although these particles digest proteins at rates similar to