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Schmidt, M., & Finley, D. (2014). Regulation of proteasome activity in health and disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1843(1), 13–25. Added by: Dr. Enrique Feoli (28/02/2026, 13:32) Last edited by: Dr. Enrique Feoli (28/02/2026, 20:05) |
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| Resource type: Journal Article DOI: 10.1016/j.bbamcr.2013.08.012 ID no. (ISBN etc.): 0167-4889 BibTeX citation key: Schmidt2014 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Proteostasis Keywords: nuclear factor erythroid derived 2-related factors, Proteasome, Protein degradation, Ubiquitin Creators: Finley, Schmidt Collection: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |
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| Abstract |
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The ubiquitin–proteasome system (UPS) is the primary selective degradation system in the nuclei and cytoplasm of eukaryotic cells, required for the turnover of myriad soluble proteins. The hundreds of factors that comprise the UPS include an enzymatic cascade that tags proteins for degradation via the covalent attachment of a poly-ubiquitin chain, and a large multimeric enzyme that degrades ubiquitinated proteins, the proteasome. Protein degradation by the UPS regulates many pathways and is a crucial component of the cellular proteostasis network. Dysfunction of the ubiquitination machinery or the proteolytic activity of the proteasome is associated with numerous human diseases. In this review we discuss the contributions of the proteasome to human pathology, describe mechanisms that regulate the proteolytic capacity of the proteasome, and discuss strategies to modulate proteasome function as a therapeutic approach to ameliorate diseases associated with altered UPS function. This article is part of a Special Issue entitled: Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |
| Notes |
Nrf1/Nrf2/SKN-1In mammals, short-term treatment of cells with proteasome inhibitors results in the upregulation of proteasomal genes. Two studies link the nuclear factor erythroid derived 2-related factors 1 (Nrf1) to the regulation of this response [100], [101], while other findings implicate Nrf2 in the stress-responsive regulation of proteasomal genes [102], [103], [104], [105]. Both transcription factors belong to the Cap‘n’Collar (CNC) transcription factor family, characterized by a unique basic leucine zipper domain. Nrf1 and Nrf2 regulate a large number of genes involved in antioxidant and xenobiotic defense [106]. A common promoter element in genes recognized by Nrf1 and Nrf2 is the antioxidant response element (ARE) [107]. They are therefore thought to have overlapping transcriptional activity, although differing strongly in their regulatory mechanisms, cellular localization, and in the phenotypes of the respective knockout mice. Nrf1 is an integral membrane protein of the endoplasmic reticulum (ER) [108], while Nrf2 is localized within the cytoplasm and at mitochondria under non-inducing conditions [109]. Nrf1 ablation in mice results in developmental defects and lethality caused by impaired liver erythropoiesis [110], while Nrf2−/− mice develop normally but are highly sensitive to oxidative stress. Nrf2−/− mice also develop neurodegenerative disorders, cancer, and autoimmune disease [111], [112]. Both Nrf proteins are regulated at the protein level via proteasome-mediated degradation. The ligases SCFβTrCP and Hrd1 have been found to be required for Nrf1 turnover [113] whereas a Cul3 family ligase that uses the KEAP protein for substrate recognition is required for regulated Nrf2 turnover [101], [114]. Although adaptive proteasome gene upregulation involves Nrf1 or Nrf2 activity, it is unclear yet whether these factors bind directly to proteasomal gene promoters. Putative AREs have been identified in proteasomal genes [100], [101], however, direct recruitment has not been shown, and a transcriptional analysis of liver-directed ablation of Nrf1 in mice did not alter the transcript levels of proteasomal genes [107].
Similarly to the response of mammalian cells to proteasome inhibition, reduced expression of proteasome genes in C. elegans activates SKN-1, the worm ortholog of Nrf1 and Nrf2 [115], and short-term proteasome inhibition leads to a compensatory upregulation of proteasomal genes via SKN-1 [116]. SKN-1 dependent upregulation of proteasomal genes is also observed upon treatment of C. elegans with H2O2 [117]. Furthermore, as described for Nrf2, SKN-1 levels are regulated by a cullin E3 ligase [118]. Interestingly, chromatin-IP (CHIP) experiments revealed that SKN-1 was bound to most proteasomal gene promoters during the L1 larval stage [119]. Recent studies suggest that the role of SKN-1 in regulating proteasome gene expression in response to proteotoxic stress is tissue specific and is coupled to the regulation of factors required for correct protein translation [116].
In summary, the data discussed provide compelling evidence that CNC transcription factors might be involved in the adaptive transcriptional regulation of proteasome genes. Furthermore, negative feedback regulation as described for Rpn4 in yeast appears to be conserved as well in higher eukaryotes (Fig. 2).
 Model for feedback regulation of proteasomal gene transcription. A) Under normal growth conditions proteasomes are expressed at basal levels. Elevated expression of proteasomal genes is prevented via rapid ubiquitin-dependent degradation of a transcription factor (TF) that recognizes specific motifs in the promoter of proteasome genes: PACE and ARE elements in yeast and mammalian cells, respectively. B) Proteotoxic stress (indicated by accumulating damaged proteins symbolized as stars) saturates existing proteasome complexes, resulting in stabilization of the transcription factor and subsequent increased expression of proteasomal genes.
Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |