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.
Highlights
Proteins are essential to the vast majority of cellular and organismal functions
Recent studies have unveiled the regulatory mechanisms of Nuclear factor erythroid-derived 2-related factor 1 (Nrf1) activation; many questions still remain unsolved
A recent study has shown that yeast Ddi1 cleaves substrate proteins in vitro only when they are tagged with long ubiquitin chains [171]
Summary
Proteins are essential to the vast majority of cellular and organismal functions. Cellular protein levels are defined by the balance among protein synthesis, folding, and degradation, and the failure to accurately coordinate these processes leads to disease [1]. The UPS degrades thousands of short-lived proteins and regulator proteins, as well as damaged and misfolded proteins, in order to regulate various cellular functions including cell cycle, DNA repair, apoptosis, immune response, signal transduction, cellular metabolism, and protein quality control [6,7,8]. To perform these functions, the maintenance of appropriate proteasome activity is essential for cellular homeostasis. We focus on the transcriptional regulation of the proteasome, especially in terms of the recent findings regarding this topic (Figure 1)
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