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Peer-reviewedCC BY 4.0Leukemia

USP8 controls proteostasis pathways in B cells and multiple myeloma

  • Almut Dufner1
  • Fabien Thery2,3
  • Gianni Monaco1,4
  • Jelena Lazarevic5
  • Oliver Gorka1
  • Nina Chevalier6
  • Marta Campos Alonso1
  • Maximilian Frosch1
  • Gerbrand J. van der Heden van Noort7
  • Kira Allmeroth8
  • Marco Prinz1,9,10
  • Olaf Groß1,9,10
10 more authors
  • Huib Ovaa7
  • Paul P. Geurink7
  • Wolfgang W. Schamel9,11,12
  • Martin S. Denzel8,13,14
  • Vigo Heissmeyer15,16
  • Benedikt Jacobs17
  • Mirle Schemionek5,18
  • Francis Impens2,3,19
  • Heiko Bruns17
  • Klaus-Peter Knobeloch1,9
19 affiliations
  1. 1Institute of Neuropathology, Medical Center–University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany
  2. 2VIB-UGent Center for Medical Biotechnology, Gent, Belgium
  3. 3Department of Biomolecular Medicine, Gent, Belgium
  4. 4Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany
  5. 5Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation University Hospital RWTH Aachen, Aachen, Germany
  6. 6Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany
  7. 7Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
  8. 8Max Planck Institute for Biology of Ageing, Cologne, Germany
  9. 9Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
  10. 10Center for Basics in NeuroModulation (NeuroModulBasics), Medical Center – University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany
  11. 11Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
  12. 12Center of Chronic Immunodeficiency CCI, Medical Center – University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany
  13. 13CECAD - Cluster of Excellence, University of Cologne, Cologne, Germany
  14. 14Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  15. 15Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
  16. 16Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Munich, Germany
  17. 17Department of Internal Medicine 5, Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  18. 18Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany
  19. 19VIB Proteomics Core, Gent, Belgium
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Abstract

Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.

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Cite

BibTeXRIS
BibTeX
@article{dufner2026usp8,
  title = {{USP8 controls proteostasis pathways in B cells and multiple myeloma}},
  author = {Almut Dufner and Fabien Thery and Gianni Monaco and Jelena Lazarevic and Oliver Gorka and Nina Chevalier and Marta Campos Alonso and Maximilian Frosch and Gerbrand J. van der Heden van Noort and Kira Allmeroth and Marco Prinz and Olaf Groß and Huib Ovaa and Paul P. Geurink and Wolfgang W. Schamel and Martin S. Denzel and Vigo Heissmeyer and Benedikt Jacobs and Mirle Schemionek and Francis Impens and Heiko Bruns and Klaus-Peter Knobeloch},
  journal = {Leukemia},
  year = {2026},
  month = aug,
  doi = {10.1038/s41375-026-03086-y},
  url = {https://doi.org/10.1038/s41375-026-03086-y},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - USP8 controls proteostasis pathways in B cells and multiple myeloma
AU  - Almut Dufner
AU  - Fabien Thery
AU  - Gianni Monaco
AU  - Jelena Lazarevic
AU  - Oliver Gorka
AU  - Nina Chevalier
AU  - Marta Campos Alonso
AU  - Maximilian Frosch
AU  - Gerbrand J. van der Heden van Noort
AU  - Kira Allmeroth
AU  - Marco Prinz
AU  - Olaf Groß
AU  - Huib Ovaa
AU  - Paul P. Geurink
AU  - Wolfgang W. Schamel
AU  - Martin S. Denzel
AU  - Vigo Heissmeyer
AU  - Benedikt Jacobs
AU  - Mirle Schemionek
AU  - Francis Impens
AU  - Heiko Bruns
AU  - Klaus-Peter Knobeloch
PY  - 2026
DA  - 2026/08/11
JO  - Leukemia
DO  - 10.1038/s41375-026-03086-y
UR  - https://doi.org/10.1038/s41375-026-03086-y
AB  - Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.
SN  - 0887-6924
SN  - 1476-5551
ER  -