2.5. Biochemical properties of proteasome activators 28γ

The third member of the PA28 protein family, proteasome activator (PA)28γ, encoded by the PSME3 gene, was discovered as nuclear Ki autoantigen about four decades ago [32]. Biochemical key features of the heptameric 11S regulator PA28γ [33–39] are summarized in Table 1. Particularly, roles in nuclear dynamics [40, 41], posttranslational modification [43–45], or contr-

Proteasome Activator 28γ: Impact on Survival Signaling and Apoptosis

http://dx.doi.org/10.5772/intechopen.74731

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Application of PA28γ as a diagnostic marker in inflammatory autoimmune or neoplastic diseases has been proposed [48, 49]. Initially identified as a nuclear autoantigen [32, 39, 50],

ibutions in apoptotic signaling are emphasized [46, 47].

Table 1. Cellular biochemistry of PA28γ.


Table 1. Cellular biochemistry of PA28γ.

activity and cleavage site preferences from s20S proteasomes [21, 22]. In concert with other intracellular proteases, combinations of both 20S isoforms, associated with 11S/19S activator complexes, contribute uniquely to processing of peptides for MHC class I antigen presentation

Degradation of ub-labeled proteasome substrates depends on 26S/30S proteasomes. These protease complexes contain either one or two 19S regulatory particles (RP) associated with the α-ring subunits of s20S or i20S CPs. The 19S RP (proteasome activator PA700) is composed of base and lid sub-complexes that reveal defined pathways of chaperone-assisted assembly [9]. The base ATPase sub-complex (subunits Rpt1–Rpt6) harbors a chaperon-like unfoldase activity [24] and is involved in substrate channeling into 26S or 30S proteasomes. The lid sub-complex enables ub-conjugate binding, as well as deubiquitination for ubiquitin recycling and substrate channeling. Assembly, composition, and topology, as well as specific biological aspects of 26S/30S proteasome genesis and function, have been reviewed compre-

The proteasome activator (PA) 28 protein family is encoded by three PSME genes. The IFNγinducible PSME1 and PSME2 genes accompany immunoproteasome expression. However, preferential association with i20S versus s20S proteasomes has not been supported by in vitro kinetics of proteasome activation [14]. Apart from their ability to form homo-heptameric proteasome-activating complexes in vitro, the PA28α and PA28β subunits prefer assembly into PA28α4β<sup>3</sup> hetero-heptamers as revealed by kinetic and structural analysis [14, 15]. PA28α4β<sup>3</sup> activates 20S proteasomes by channeling, regulating the width of the narrow orifice, and excluding natively folded protein substrates. The control of substrate import and export of peptide products, possibly as a molecular sieve, or due to allosteric regulation of proteasomes by PA28α4β<sup>3</sup> may affect proteasomal processivity and quality of peptide products [27, 28].

Double knockouts of the IFNγ-inducible members of the PSME1 and PSME2 genes [29] were examined with respect to immunological functions and immunoproteasome assembly. Substantiating the role of so-called hybrid proteasomes (PA28α4β3-20S proteasomes) [30, 31], it was found that association of 26S proteasomes with PA28α4β<sup>3</sup> increased proteasomal activity and presentation of particular antigens [29]. However, PA28αβγ-null mice showed normal antigen presentation with some antigens and impairment with others. Based on these observations, it has been stated that PA28αβγ is not a prerequisite for antigen processing in general,

The third member of the PA28 protein family, proteasome activator (PA)28γ, encoded by the PSME3 gene, was discovered as nuclear Ki autoantigen about four decades ago [32]. Biochemical key features of the heptameric 11S regulator PA28γ [33–39] are summarized in Table 1.

of self or foreign antigens [23].

hensively by others [20, 25, 26].

2.3. 19S regulatory particle and 26S/30S proteasomes

74 Current Understanding of Apoptosis - Programmed Cell Death

2.4. Proteasome activator 28αβ and MHC class I antigen presentation

but seems to be essential for the processing of certain CTL epitopes [23].

2.5. Biochemical properties of proteasome activators 28γ

Particularly, roles in nuclear dynamics [40, 41], posttranslational modification [43–45], or contributions in apoptotic signaling are emphasized [46, 47].

Application of PA28γ as a diagnostic marker in inflammatory autoimmune or neoplastic diseases has been proposed [48, 49]. Initially identified as a nuclear autoantigen [32, 39, 50], context-dependent cytosolic presence has also been reported. In breast cancer, PA28γ accumulates in nuclei, whereas in pancreatic cancer cells, PA28γ emerges in the cytosol [51], indicating that cellular context generates diverse scenarios with respect to subcellular localization and function of PA28γ. Nuclear-cytosolic shuttling, mediated by posttranslational modification, depends on cell types and conditions [44, 52, 53]. Sumoylation of amino-terminal lysine residues K6/14/12 by PIAS1 (E3) enhances cytosolic localization and increases stability, presumably prerequisites for proteasome association and substrate recognition [44]. Contrarily, acetylation at K195 by CREB-binding protein (CBP) favors assembly of nuclear PA28γ. Deacetylation by sirtuin 1 (SirT1) has been demonstrated in mammalian cells. Since K6 and K14 residues can be acetylated as well, competition with sumoylation cannot be excluded [45]. Furthermore, phosphorylation of PA28γ by protein kinase MEKK3 resulted in a concomitant increase of PA28γ levels in Cos cells [43]. Stress kinases Chk2 and ATM have been reported to phosphorylate PA28γ, thereby affecting protein-protein interactions (PPI) and functions in DNA damage response [42].
