Maintaining proteome functionality is a major challenge that the cell must resolve in order to survive the diverse conditions that it encounters. Changes in biophysical conditions and post-translational modifications all impact the correct folding of proteins, and cellular machineries have evolved to maintain proteome integrity. Promiscuous interactions of misfolded proteins are highly toxic to the cell and manifest in various pathologies
[1]; therefore, restoring the proper configuration of misfolded proteins by chaperones, reducing enzymes and more constitutes a salvation pathway. In contrast, degradation pathways such as the ubiquitin–proteasome system (UPS) or the lysosomal pathway eliminate the toxicity of misfolded proteins by proteolytic degradation
[2]. The 26S proteasome is the central module of the UPS to which all designated proteins, usually ubiquitinated with suitable configurations of ubiquitin, are delivered. The 26S proteasome is composed of a 20S catalytic particle and a 19S regulatory particle that enables recognition, deubiquitination and unfolding of a UPS substrate. In order to ensure the functionality of the basic 26S proteasome module, various modes of regulation exist in order to maintain functionality during acute and chronic conditions. We can artificially divide these modifications into several categories, including quantitative and qualitative changes in proteasome subunits (executed by transcriptional
[3][4][5][3,4,5] and translational
[6] programs as well as post-translational modifications of proteasome subunits
[7]) and changes in the composition of specific subunits, as exemplified in the case of the immunoproteasome (20Si) and the thymus proteasome (20St). In this mode of regulation, the exchange of catalytic subunits in response to acute signaling (IFN-γ)
[8][9][8,9] or unique surroundings
[10][11][10,11] enables modification of the proteasome to a more suitable peptide output. Another mode of regulation consists of alternating the entire cap composition. Alternative caps such as PA200 enable the engagement of the proteasome with specific substrates
[12][13][12,13], while the PA28 (11S) enables proteasome modulation during specific conditions such as IFN-γ
[9][14][15][9,14,15]. The fourth mode of regulation that is diverse and continuously engaged with the proteasome involves shuttling factors. These accessory factors typically consist of a proteasome binding domain that usually consists of a ubiquitin-like (UBL) domain that binds one of the proteasome ubiquitin receptors and several ubiquitin binding domains (UBD) that account for ubiquitin chain affinity and specificity (for reviews, see
[16][17][18][16,17,18]). The UBA–UBL mode of substrate delivery to the proteasome increases the diversity and flux of UPS substrates
[19], induces proteasome activation
[20] and supports the formation of liquid–liquid phase separation of proteasomes
[21][22][21,22].
Originally identified as an arsenite inducible gene
[23], AIRAP/Zfand2a was subsequently found to bind proteasomes with unique biochemical characteristics
[24]. These include AIRAP–proteasome integrity in the absence of ATP and enhanced peptide hydrolysis. Unlike other proteasomal adaptors, AIRAP–proteasome binding is not obtained via UBA domains, nor does it bind ubiquitin. AIRAP knockout cells accumulate higher polyubiquitin levels in response to arsenite exposure (typical of UPS impairment) and proteasomes acquired from the knockout cells contain higher levels of polyubiquitinated substrates
[24]. These findings rule out AIRAP’s function as a shuttle factor but rather indicate it as a proteasome adaptor required for the efficient processing of UPS substrates by the proteasome upon arsenite-inflicted inhibition. In line with this notion, AIRAP expression was found to be induced upon proteasomal inhibition
[25]; thus, AIRAP’s role and gene expression programing point towards a mechanistic function in retaining proteasomal function upon inhibitory conditions, yet the mechanistic details of AIRAP function have not been revealed.