ArticleScientific reports2023
The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis.
Article in Scientific reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- The ubiquitin-proteasome system and autophagy as guardians of the cellular proteome.FEBS letters · 2026Review
- Nrf1 coordinates proteasome activity and autophagy to maintain cardiac proteostasis.Communications biology · 2026Article
- Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain.Pharmaceutics · 2026Review
- Micro- and nanoplastics remodel the autophagy-lysosomal axis and mitochondrial function in primary human monocytes.Frontiers in immunology · 2026Article
- Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.Frontiers in cellular neuroscience · 2026Review
- NOX-NOS crosstalk in the liver-brain axis: Novel insights for redox regulation and neurodegenerative diseases.Redox biology · 2025Review
- Article
- From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences.International journal of molecular sciences · 2025Article
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- Multiple-omics analysis of aggrephagy-related cellular patterns and development of an aggrephagy-related signature for hepatocellular carcinoma.World journal of surgical oncology · 2025Article
- Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs.ACS pharmacology & translational science · 2025Review
- Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.International journal of molecular sciences · 2025Review
- NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.Frontiers in molecular neuroscience · 2025Review
- Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories.Cell stress · 2025Review
- Ubiquitination-mediated protein homeostasis in cardiovascular diseases: molecular mechanisms and therapeutic opportunities.American journal of cardiovascular disease · 2025Review
- Emerging Signatures of Hematological Malignancies from Gene Expression and Transcription Factor-Gene Regulations.International journal of molecular sciences · 2024Article
- Ferroptosis regulation by Cap'n'collar family transcription factors.The Journal of biological chemistry · 2024Review
- Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans.PLoS biology · 2024Article
- Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.The Journal of cell biology · 2024Article
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Authors and funding
10 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ubiquitin‒proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function activates aggrephagy remain poorly understood. Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 (NFE2L1) in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62/SQSTM1 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of Ser403 in p62. Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired.
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