Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma
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.
Authors
- Jingjing Gao (ORCID: https://orcid.org/0000-0001-8608-6949)
- Julian Mintseris
- Stephen J. Elledge (ORCID: https://orcid.org/0000-0001-7923-6283)
- Nolan Kamitaki (ORCID: https://orcid.org/0000-0003-0614-0189)
- Sirano Dhe‐Paganon (ORCID: https://orcid.org/0000-0003-0824-5929)
- Anna Besschetnova (ORCID: https://orcid.org/0000-0003-3623-1997)
- Christopher Nardone (ORCID: https://orcid.org/0000-0002-1705-5310)
- Lucy Ort
- Mariateresa Fulciniti (ORCID: https://orcid.org/0000-0002-1432-9742)
- Michael E. Greenberg (ORCID: https://orcid.org/0000-0003-1380-2160)
- Matthew C. J. Yip (ORCID: https://orcid.org/0000-0002-2505-9987)
- Sichen Shao (ORCID: https://orcid.org/0000-0003-2679-5537)
- Hyuk‐Soo Seo (ORCID: https://orcid.org/0000-0003-0646-2102)
- Steven P. Gygi (ORCID: https://orcid.org/0000-0001-7626-0034)
- Xin Gu (ORCID: https://orcid.org/0009-0009-3207-012X)
- Nikhil Munshi (ORCID: https://orcid.org/0000-0002-8397-100X)
- Milen Negasi
Institutions
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1016/j.molcel.2025.05.030
- Citations
- 12
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- National Science Foundation
- David and Lucile Packard Foundation
- Howard Hughes Medical Institute
- American Heart Association
- Damon Runyon Cancer Research Foundation
- National Institutes of Health