1. Introduction

Posttranslational modification and regulated intracellular proteolysis are intimately linked with regulation of proliferation, differentiation, and apoptosis. Aforementioned survival processes depend on the steady-state levels of proteins acting as molecular switches of signaling networks and regulated proteolytic systems activating or removing such switches. Proteasomal protein degradation bifurcates into ubiquitin-dependent pathways, namely, the ubiquitin proteasome system (UPS) and ubiquitin-independent proteasomal protein (UIPP) degradation pathways [1]. Due to the modular structure of the proteasomal proteolytic system, composed of 20S proteasomes, 19S regulatory particles (RP), and 11S proteasome activator 28 (PA28) subtypes, it is challenging to identify definite relations between 20S proteasomes, regulator-associated proteasomes, and their substrates.

of thioester-linked Ub/UBL mostly to lysine residues of substrate proteins. Since ubiquitin contains seven putative conjugation sites, linear or branched Ub conjugates can be formed by isopeptide bonds creating individual barcodes. Processing of conjugates, either as a requirement for substrate channeling into proteasomes or for fine tuning the barcode information, is performed by cysteine proteases of the deubiquitinase (DUB) protein family [7]. The resulting barcodes are guiding proteins into different fate decisions, namely, affecting subcellular locations (UBL:SUMO), enzymatic activity (UBL:NEDD8), or 26S/30S proteasomal turnover (UBL:

Proteasome Activator 28γ: Impact on Survival Signaling and Apoptosis

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

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Ubiquitin-K48 conjugates are mostly used as degradation signal [5] that can be recognized by 19S regulatory particles (PA700) attached to one or both ends of 20S proteasomes, either

The term "20S proteasome" encompasses variant isoforms of compartmentalized, barrel shaped 700 kDa core proteases (CP) of α1–7β1–7β1–7α1–<sup>7</sup> stoichiometry [10]. Six active site β-subunits of the catalytic chamber are processed from zymogenic β1, β2, and β5 precursor subunits during standard (s20S) proteasome assembly, establishing the amino-(N)-terminal threonine nucleophiles central to the catalytic mechanism [11]. Proteasomes reveal cleavage site preferences for hydrophobic, basic, and acidic P1 residues resembling specificities of prototypic proteases (chymotrypsin-like (CHYT), trypsin-like (TRYP), caspase-like (CASP). Typically, for a compartmentalized protease, access to the active sites is regulated by gated pores, formed by the amino-terminal chains of α-ring subunits [12]. The narrow orifice formed by the α-rings restricts access of most native proteins. Therefore, unstructured protein regions or protein unfolding is a prerequisite for substrate channeling, conducted by 19S 11S

Due to tissue-specific or cytokine-inducible expression of proteasomal active site subunits [16, 17], a high diversity of 20S proteasome complexes is principally available to associate with proteasome activators (PA) such as PA700 (19S), PA28αβ, or PA28γ (11S). As reviewed elsewhere [9, 10], proteasomes have been purified and biochemically characterized from various sources, most recently discovering the unique properties of 20S proteasomes from thymus (t20S) [18], a discovery highly relevant for the understanding of positive selection of T cells [19]. Constitutively, expressed standard 20S proteasomes (s20S) and immune proteasomes (i20S) have been compared with respect to their different assembly kinetics, half-lives, and

The pro-inflammatory cytokine interferon-γ (IFN-γ) modulates the composition of the immunoproteasome (i20S), due to the expression of zymogens (pro-subunits) of inducible active site subunits (iβ1, iβ2, iβ5). During POMP-dependent proteasome assembly in proximity to the ER, active site subunits of constitutively expressed proteasomes (s20S) are replaced by the inducible subunits, forming immunoproteasomes (i20S). The i20S complexes reveal faster assembly (about 21 versus 80 min) and shorter half-lives (27 versus 133 h) and differ in

ubiquitin) [3–5, 8].

2.2. 20S proteasomes

2.2.1. Core proteases of UIPP and UPS

proteasome activators [12–15].

catalytic capabilities [20].

forming 26S or 30S proteasomes, respectively [9].

Among 11S regulators, proteasome activator 28γ (PA28γ) has earned remarkable attention, due to its pronounced overexpression in cancer and its functional relation to tumor biology. Several evidences indicate that PA28γ, in addition to its role as a 20S proteasome activator and as a putative substrate recognition module, might also act as a modulator of E3 ubiquitin ligases. Since the first contributions of PA28γ to UIPP have been reviewed a decade ago [2], a reevaluation of proteasome biology with a focus on the intrinsic pathway of apoptosis seems justified. Growing knowledge about the remarkable efforts of various proteasomal proteolytic systems in cell survival will improve the mechanistic knowledge for target definition and specific drug design to counterstrike cancer [3].
