Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma
Open accessPublished version of a preprint
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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Cites
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“42 Midnolin mRNA was selectively downregulated approximately 4-to 5-fold in MM cell lines compared with those derived from solid tumors, lymphomas, or leukemias (Figure 5A).”
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- Authors
- Nardone, C., Gao, J., Seo, H.-S., Mintseris, J., Ort, L., Yip, M. C. J., Negasi, M., Besschetnova, A. K., Kamitaki, N., Gygi, S. P., Dhe-Paganon, S., Munshi, N. C., Fulciniti, M., Greenberg, M. E., Shao, S., Elledge, S. J., & Gu, X.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- VA Boston Healthcare System (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shao, Sichen
- Elledge, Stephen J.
- Gu, Xin
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-07
- Volume
- 85
- Issue
- 13
- Pages
- 2597-2609.e11
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC12291620
- OpenAlex
- W4411370036
- Cited by
- 22
- References
- 6
- Citations by year
- 2026: 15 · 2025: 7
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation (DRG-2469-22)
- American Heart Association Inc (287375208)
- Howard Hughes Medical Institute
- National Institutes of Health (GM97645, R01 NS115965, AG11085, R01073277, T32 HG002295, CA155258-10)
- National Science Foundation
- David and Lucile Packard Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Keywords
- proteasome, multiple myeloma, ubiquitin-like proteins, nuclear localization signal, transcription factor degradation, proteasome structure
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