ArticleMolecular cell2025
Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.
Article in Molecular cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- Molecular basis of ubiquitin-independent recognition and degradation of ODC/Antizyme by the 26S proteasome.bioRxiv : the preprint server for biology · 2026Article
- The ubiquitin-proteasome system and autophagy as guardians of the cellular proteome.FEBS letters · 2026Review
- Survey of the human proteostasis network: the ubiquitin-proteasome system.bioRxiv : the preprint server for biology · 2026Article
- Structural dynamics of the midnolin-proteasome during ubiquitin-independent substrate turnover.Nature communications · 2026Article
- Proteasomal control of transcription factors: mechanisms, regulation and dysregulation.Cellular and molecular life sciences : CMLS · 2026Review
- Sequential RNA polymerase II activation drives human hematopoiesis.Cell reports · 2026Article
- Structure of the TXNL1-bound proteasome.Nature structural & molecular biology · 2025Article
- Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.Molecular cell · 2025Article
- Structural insights into the ubiquitin-independent midnolin-proteasome pathway.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Proteasome: Role in T Cell Function Regulation.International journal of biological sciences · 2025Review
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17 authors.
Funding
Abstract
The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome complex, revealing how established proteasomal components are repurposed to enable a unique form of proteolysis. While the proteasomal subunit PSMD2/Rpn1 binds to ubiquitinated or ubiquitin-like (Ubl) proteins, we discover that it also interacts with the midnolin nuclear localization sequence, elucidating how midnolin's activity is confined to the nucleus. Likewise, PSMD14/Rpn11, an enzyme that normally cleaves ubiquitin chains, surprisingly functions non-enzymatically as a receptor for the midnolin Ubl domain, positioning the substrate-binding Catch domain directly above the proteasomal entry site to guide substrates into the proteasome. Moreover, we demonstrate that midnolin downregulation is critical for the survival of myeloma cells by stabilizing the transcription factor substrate IRF4. Our findings uncover the mechanisms underlying the midnolin-proteasome pathway and midnolin downregulation as a driver of multiple myeloma.
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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 Socratic graph.