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PreprintCited by 22Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsMultiple Myeloma Research and Treatments

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma

Open access
Nardone, Christopher, Gao, Jingjing, Seo, Hyuk-Soo, Mintseris, Julian, Ort, Lucy, Yip, Matthew C. J., Negasi, Milen, Besschetnova, Anna K., Kamitaki, Nolan, Gygi, Steven P., Dhe-Paganon, Sirano, Munshi, Nikhil, Fulciniti, Mariateresa, Greenberg, Michael E., Shao, Sichen, Elledge, Stephen J., Gu, Xin·2025·Molecular Cell
DOI 10.1101/2025.02.22.639686PMC PMC12291620

Preprint — published as 10.1016/j.molcel.2025.05.030 · Paper page

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Abstract

Summary: 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 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 ubiquitin-like (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 promoting the expression of its 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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Metadata

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., 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)
  • Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
  • VA Boston Healthcare System (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Shao, Sichen
  • Elledge, Stephen J.
  • Gu, Xin
ORCID
Venue
Molecular Cell
Publisher
openRxiv
Published
2025-02-23
Volume
85
Issue
13
Pages
2597-2609.e11
ISSN
1097-2765 (ISSN-L)
DOI
10.1101/2025.02.22.639686
PMC
PMC12291620
OpenAlex
W4411370036
Cited by
22
References
1
Citations by year
2026: 15 · 2025: 7
FWCI
6.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Science Foundation
  • David and Lucile Packard Foundation
  • Howard Hughes Medical Institute
  • American Heart Association (287375208)
  • Damon Runyon Cancer Research Foundation (DRG-2469-22)
  • National Institutes of Health (R01073277, GM97645, CA155258-10)
  • National Institute on Aging (R01AG073277, R01AG011085)
  • National Heart, Lung, and Blood Institute (R01HL177823)
  • National Human Genome Research Institute (T32HG002295)
  • National Cancer Institute (P01CA155258)
  • National Institute of Neurological Disorders and Stroke (R01NS115965)
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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