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

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