Figure 12. A bidirectional regulatory feedback circuit exists between Nrf1 and the 26S proteasome.

(a) A model is proposed, based on our findings (refs ²³, ²⁴, ²⁵, ²⁶,³⁴,³⁶ and this study) and those of others (refs ²,³,²⁹, ³⁰, ³¹,³⁷,⁴⁰), in order to explain the regulatory feedback circuit between Nrf1 and the 26S proteasome. The 120-kDa Nrf1 glycoprotein is retrotranslocated through the p97/VCP-driven pathway from the ER into the nuclo/cytoplasm where it is deglycosylated to yield an active 95-kDa isoform. The latter deglycoprotein is proteolytically processed to generate a cleaved 85-kDa Nrf1 isoform by the 26S proteasome that is activated by proteasome inhibitors through a feedback loop. In turn, transcriptional expression of the 26S proteasome and p97/VCP complexes is regulated by the 95-kDa and/or 85-kDa Nrf1 isoforms before the CNC-bZIP transcription factor is subjected to further proteasome-mediated processing that creates small Nrf1 isoforms of between 55-kDa and 25-kDa. Such small polypeptides may also be produced by in-frame translation of long Nrf1 mRNA transcripts and subsequently further degraded by the proteasome. (b) Schematic representation of a bidirectional regulatory feedback circuit exists between Nrf1 and the 26S proteasome. The transcriptional expression of 26S proteasomal subunits (e.g. PMSA4 and PMSB6) is regulated predominantly by Nrf1 (see refs ²,³,²⁹, ³⁰, ³¹,³⁷,⁴⁰). In turn, different doses of the proteasomal inhibitors MG132 and CI/ALLN exert opposing effects on the activity of Nrf1 to mediate expression of genes encoding proteasomal subunits. Specifically, at low doses, MG132 and CI/ALLN increase activity of Nrf1-target proteasomal subunit gene expressions by increasing the levels of the active 95- and/or 85-kDa Nrf1 isoforms, whereas high doses of MG132 and CI/ALLN inhibit Nrf1-mediated transcription by increasing the levels of the 36-kDa Nrf1γ and 25-kDa Nrf1δ dominant-negative isoforms. However, the detailed rational mechanism(s) of this bi-phasic response remains to be determined. In addition, further mechanistic study is warranted to identify which proteases enable the endoproteolytic processing of either 120-kDa or 95-kDa Nrf1 proteins to yield the cleaved 85-kDa isoform.