ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond

Abstract

Protein folding is a substantively error prone process, especially when it occurs in the endoplasmic reticulum (ER). The highly exquisite machinery in the ER controls secretory protein folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol; these misfolded proteins are then degraded by the ubiquitin–proteasome system termed as the ER-associated degradation (ERAD). The 26S proteasome is a multisubunit protease complex that recognizes and degrades ubiquitinated proteins in an ATP-dependent manner. The complex structure of the 26S proteasome requires exquisite regulation at the transcription, translation, and molecular assembly levels. Nuclear factor erythroid-derived 2-related factor 1 (Nrf1; NFE2L1), an ER-resident transcription factor, has recently been shown to be responsible for the coordinated expression of all the proteasome subunit genes upon proteasome impairment in mammalian cells. In this review, we summarize the current knowledge regarding the transcriptional regulation of the proteasome, as well as recent findings concerning the regulation of Nrf1 transcription activity in ER homeostasis and metabolic processes.

Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors

“…The ubiquitin-proteasome system (UPS), the primary mechanism by which proteins are degraded in the cytoplasm and nucleus, determines cellular protein levels and quality in coordination with autophagy and chaperon-mediated protein folding [29,30,35,36]. Cancer cells express massive amounts of both wild-type and mutant proteins to sustain their growth and high metabolic rate.…”

“…Following the coordinated induction of 33 proteasome subunit genes, these subunits are tightly assembled via complex mechanisms [28][29][30]36]. The 20S proteasome includes an α-ring and a β-ring that contain α1-α7 and β1-β7 subunits, respectively.…”

“…Five chaperones also regulate the assembly of the base and lid. Aside from the 19S proteasome, other proteasome regulators, such as proteasome activator (PA) 28αβ, PA28γ, PA200, ECP29, and PSMF1, are also known to bind to the 20S proteasome, forming alternative proteasome complexes that modulate divergent types of proteasomal degradation [29,30,44].…”

“…On the basis of the molecular evolution of the CNC family proteins as determined by their protein structures, NRF3 is a rather close homolog of NRF1 [ 88 ]. The protein structure of NRF3 is similar to that of NRF1; Nrf1 also possesses the NHB1/2 domain, and its transcriptional function is therefore similarly regulated by both DDI2 and NGLY ( Figure 5 A) [ 29 , 89 , 90 ]. NRF1 is ubiquitously expressed in whole tissues.…”

“…(B) Schematic representation of the molecular mechanisms of proteasome assembly. The 26S proteasome comprises 20S and 19S proteasomes containing 66 subunits[28][29][30]. The assembly of each proteasome complex is tightly regulated in a coordinated manner by distinct chaperones.…”