PA28γ: New Insights on an Ancient Proteasome Activator

Abstract

PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero (PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28α and PA28β seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28αβ favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28γ seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28γ has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28αβ, most of these diverse biological functions of PA28γ seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28γ, which are likely to account for its various and complex biological functions and highlight the common features with the PA28αβ paralog.

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention

“…As mentioned above, the reversible binding of activators (i.e., 19S and PA200) to either one or both α subunit rings of the 20S is another important level of proteasome organization that contributes to the overall heterogeneity of proteasomes ( Figure 1 ) [ 15 ]. Besides the 19S, the best-characterized regulatory particle is PA28 (i.e., 11S regulatory particle), which preferentially binds the immunoproteasome, forming the PA28/i20S complex as discussed further (see Section 3.2 ) [ 16 , 78 ]. The binding of activators increases the proteolytic activity of the catalytic core, promoting the α-gate opening, influencing the substrate specificity of the complex, and, more importantly, affecting the repertoire of cleavage products [ 15 ].…”

“…As mentioned in the previous sections, besides the 19S, the second most common proteasome regulator is the ATP and ubiquitin-independent PA28 activator family that includes three highly homologous, ~28 kDa subunits, α, β, and γ, which form a ring-shaped 200 kDa multimeric complex (i.e., PA28αβ and PA28γ). This complex binds, in an ATP-dependent manner, to the two free ends of the 20S or associates with a single-capped 26S (19S:20S), forming the hybrid proteasome 19S–20S–PA28 [ 16 , 128 , 129 , 130 , 131 ]. This hybrid assembly hydrolyses tri- and tetra-peptides at a higher rate than constitutive 26S.…”

“…This hybrid assembly hydrolyses tri- and tetra-peptides at a higher rate than constitutive 26S. The structure, function, and mechanism through which it induces the 20S gate opening was recently extensively and more competently reviewed [ 16 ]. PA28α and PA28β, which show a prevalent cytosolic localization, are upregulated by IFNγ and other proinflammatory cytokines.…”

“…Indeed, the UPS carries out multiple functions in cells and in the onset and progression of different human pathologies spanning from neurodegeneration to cancer [ 15 ]. A major role in antigen processing is covered by a specialized and inducible form of proteasome (i.e., the multi-catalytic machine which degrades ubiquitinated proteins) named “immunoproteasome” [ 16 ]. This review focuses on immunoproteasome, its involvement in antigen generation, and on the therapeutic implications of its modulation to halt cancer progression.…”

PA28γ–20S proteasome is a proteolytic complex committed to degrade unfolded proteins

“…In vivo PA28αβ exerts a clear action of stimulation of MHC class I antigen presentation, although this activity is restricted to only some epitopes [25]. On the contrary, PA28γ forms homoheptameric rings that are located exclusively in the nucleus and which are not induced (and even reduced) by γ-interferon [26]. PA28γ was initially reported to exclusively enhance the trypsin-like activity of proteasomes [27,28], but additional data indicates that it can also stimulate the other two (i.e., chymotrypsin-and caspaselike) peptidase activities [29][30][31].…”