Dynamic Regulation of Proteasome Expression

Abstract

The 26S proteasome is a multisubunit complex that catalyzes the degradation of ubiquitinated proteins. The proteasome comprises 33 distinct subunits, all of which are essential for its function and structure. Proteasomes are necessary for various biological processes in cells; therefore, precise regulation of proteasome expression and activity is essential for maintaining cellular health and function. Two decades of research revealed that transcription factors such as Rpn4 and Nrf1 control expression of proteasomes. In this review, we focus on the current understanding and recent findings on the mechanisms underlying the regulation of proteasome expression, as well as the translational regulation of proteasomes.

Keywords: NRF1; immunoproteasome; proteasome; thymoproteasome; transcription.

Figure 1

The architecture of the 26S proteasome. The human 26S proteasome structures obtained by cryo-electron microscopy. Because Rpn13 is not included in the cryo-EM data, the structural data of Rpn13 obtained by solution NMR was also used. The structural data were derived from RCSB PROTEIN DATA BANK (PDB ID: 6MSK and 5YMY).

Figure 2

The transcription factor Nrf1 is processed and activated by DDI2 under conditions of proteasomal dysfunction. Under normal conditions, Nrf1 is degraded via the ERAD pathway. In proteasomal dysfunction, Nrf1 is processed by the aspartic protease DDI2; the mature form of Nrf1 then translocates to the nucleus to induce expression of proteasome genes.

Figure 3

Regulation of the expression of proteasome genes. Proteasome dysfunction and mTORC1 activation induce transcription of proteasomal genes in an Nrf1-dependent manner. MAP kinase and ribosomal dysfunction are suggested to regulate translation of proteasomal mRNAs.

Figure 4

Genomic organization of the subunits of the immunoproteasome and thymoproteasome in humans. The genes encoding β1i (PSMB9) and β5i (PSMB5) are located in the MHC region and adjacent to the TAP1 and TAP2 genes. The β2i gene (PSMB10) is located outside the region. The gene encoding the thymoproteasome subunit β5t (PSMB11) is located close to the β5 gene (PSMB5).