ArticleBlood advances2022
Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival.
Article in Blood advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Exploiting tumor lineage features for precision cancer therapy.Trends in cancer · 2026Review
- K48-ubiquitin-dependent proteases cut-up post-ER proteins.Nature communications · 2026Article
- The role of OTUD1-mediated deubiquitination in disease pathogenesis: from molecular mechanisms to clinical translation.Frontiers in immunology · 2026Review
- The emerging role of ubiquitin-proteasome system dysfunction in the pathogenesis of perioperative neurocognitive disorders: a narrative review.Frontiers in behavioral neuroscience · 2026Review
- The role of antioxidants in multiple myeloma: diagnostic, prognostic, and therapeutic applications: a narrative review.Therapeutic advances in hematology · 2026Review
- Nuclear respiratory factor 1 promotes cell survival in multiple myeloma under proteasome inhibition therapy.Blood · 2025Article
- Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.Molecular biology of the cell · 2025Article
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- LAPTM5 Confers the Resistance to Venetoclax via Promoting the Autophagosome-Lysosome Fusion in Multiple Myeloma.Journal of cellular and molecular medicine · 2025Article
- Article
- Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- Article
- Proteotoxic stress and the ubiquitin proteasome system.Seminars in cell & developmental biology · 2024Review
- Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.International journal of hematology · 2024Article
- Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2.bioRxiv : the preprint server for biology · 2023Article
- Article
- The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis.Scientific reports · 2023Article
- α-Tocotrienol and Redox-Silent Analogs of Vitamin E Enhances Bortezomib Sensitivity in Solid Cancer Cells through Modulation of NFE2L1.International journal of molecular sciences · 2023Article
- Aspartyl Protease Inhibitors as Anti-Filarial Drugs.Pathogens (Basel, Switzerland) · 2022Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base of MM sensitivity to agents that perturb proteostasis, such as proteasome inhibitors (PIs), the mainstay of modern-day myeloma therapy. De novo and acquired PI resistance are important clinical limitations that adversely affect prognosis. The molecular mechanisms underpinning PI resistance are only partially understood, limiting the development of drugs that can overcome it. The transcription factor NRF1 is activated by the aspartic protease DNA damage inducible 1 homolog 2 (DDI2) upon proteasome insufficiency and governs proteasome biogenesis. In this article, we show that MM cells exhibit baseline NRF1 activation and are dependent upon DDI2 for survival. DDI2 knockout (KO) is cytotoxic for MM cells, both in vitro and in vivo. Protein structure-function studies show that DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome activity recovery upon irreversible proteasome inhibition and, thereby, increasing sensitivity to PIs. Add-back of wild-type, but not of catalytically dead DDI2, fully rescues these phenotypes. We propose that DDI2 is an unexplored promising molecular target in MM by disrupting the proteasome stress response and exacerbating proteotoxicity.
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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.