ArticleACS central science2017
Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity.
Article in ACS central science, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers.
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Who cites it
114 citing papers in PubMed, 188 citations in OpenAlex.
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.PLoS genetics · 2026Article
- ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.bioRxiv : the preprint server for biology · 2026Article
- Nrf3: an emerging player in cancer, inflammation, and cellular homeostasis.Molecular biology reports · 2026Review
- Progressive neurodegeneration, motor decline, and premature mortality in aging Ngly1 deficient rats.Orphanet journal of rare diseases · 2026Article
- NFE2L1/Nrf1 forms a coactivator complex post-peptide:Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.Advances in experimental medicine and biology · 2026Review
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.bioRxiv : the preprint server for biology · 2025Article
- Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.Molecular biology of the cell · 2025Article
- The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.The Journal of experimental medicine · 2025Article
- NGLY1 as an Emerging Critical Modulator for Neurodevelopment and Pathogenesis in the Brain.International journal of molecular sciences · 2025Review
- Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.PLoS genetics · 2025Article
- The HCV-Dependent Inhibition of Nrf1/ARE-Mediated Gene Expression Favours Viral Morphogenesis.Viruses · 2025Article
- Article
- Impaired Proteostasis is Linked to Neurological Pathology in a Zebrafish NGLY1 Deficiency Model.Journal of inherited metabolic disease · 2025Article
- Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.PLoS genetics · 2025Article
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- All-stage targeted nanodiscs for glioma treatment by inducing cuproptosis and apoptosis of cancer cells and cancer stem cells.Asian journal of pharmaceutical sciences · 2025Article
- Exosome-transmitted HSPA9 facilitates bortezomib resistance by targeting TRIP13/USP1 signaling in multiple myeloma.Cell communication and signaling : CCS · 2025Article
- Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis.Cell death and differentiation · 2025Article
- Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories.Cell stress · 2025Review
54 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 6 institutions in 3 countries.
Funding
Abstract
Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This "bounce-back" response is achieved through a unique mechanism. Nrf1 is constitutively translocated into the ER lumen, N-glycosylated, and then targeted for proteasomal degradation via the ER-associated degradation (ERAD) pathway. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Under these conditions, Nrf1 is inactive in regulating proteasome subunit gene expression in response to proteasome inhibition. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. Thus, NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.