Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration.
Cell Nucleus
/ metabolism
Endoplasmic Reticulum
/ metabolism
Endoplasmic Reticulum-Associated Degradation
/ genetics
Gene Expression
/ genetics
Gene Expression Regulation
/ genetics
HEK293 Cells
Humans
NF-E2-Related Factor 1
/ genetics
Proteasome Endopeptidase Complex
/ genetics
Transcription Factors
/ metabolism
Transcription, Genetic
/ genetics
Journal
Molecular biology of the cell
ISSN: 1939-4586
Titre abrégé: Mol Biol Cell
Pays: United States
ID NLM: 9201390
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
entrez:
14
9
2020
pubmed:
15
9
2020
medline:
23
6
2021
Statut:
ppublish
Résumé
The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER--associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.
Identifiants
pubmed: 32924844
doi: 10.1091/mbc.E20-04-0238
pmc: PMC7550695
doi:
Substances chimiques
NF-E2-Related Factor 1
0
NFE2L1 protein, human
0
Transcription Factors
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2158-2163Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM132396
Pays : United States
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