{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Neuropathology, Medical Center–University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany",
    "VIB-UGent Center for Medical Biotechnology, Gent, Belgium",
    "Department of Biomolecular Medicine, Gent, Belgium",
    "Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany",
    "Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation University Hospital RWTH Aachen, Aachen, Germany",
    "Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany",
    "Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands",
    "Max Planck Institute for Biology of Ageing, Cologne, Germany",
    "Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany",
    "Center for Basics in NeuroModulation (NeuroModulBasics), Medical Center – University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany",
    "Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany",
    "Center of Chronic Immunodeficiency CCI, Medical Center – University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany",
    "CECAD - Cluster of Excellence, University of Cologne, Cologne, Germany",
    "Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany",
    "Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany",
    "Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Munich, Germany",
    "Department of Internal Medicine 5, Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany",
    "Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany",
    "VIB Proteomics Core, Gent, Belgium"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Almut Dufner",
      "orcid": "0000-0002-9950-0691"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Fabien Thery"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Gianni Monaco"
    },
    {
      "affs": [
        4
      ],
      "name": "Jelena Lazarevic"
    },
    {
      "affs": [
        0
      ],
      "name": "Oliver Gorka",
      "orcid": "0000-0002-8245-3008"
    },
    {
      "affs": [
        5
      ],
      "name": "Nina Chevalier",
      "orcid": "0000-0002-1924-9530"
    },
    {
      "affs": [
        0
      ],
      "name": "Marta Campos Alonso",
      "orcid": "0009-0008-7356-6095"
    },
    {
      "affs": [
        0
      ],
      "name": "Maximilian Frosch",
      "orcid": "0000-0002-5418-0962"
    },
    {
      "affs": [
        6
      ],
      "name": "Gerbrand J. van der Heden van Noort"
    },
    {
      "affs": [
        7
      ],
      "name": "Kira Allmeroth"
    },
    {
      "affs": [
        0,
        8,
        9
      ],
      "name": "Marco Prinz",
      "orcid": "0000-0002-0349-1955"
    },
    {
      "affs": [
        0,
        8,
        9
      ],
      "name": "Olaf Groß"
    },
    {
      "affs": [
        6
      ],
      "name": "Huib Ovaa"
    },
    {
      "affs": [
        6
      ],
      "name": "Paul P. Geurink"
    },
    {
      "affs": [
        8,
        10,
        11
      ],
      "name": "Wolfgang W. Schamel"
    },
    {
      "affs": [
        7,
        12,
        13
      ],
      "name": "Martin S. Denzel"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Vigo Heissmeyer"
    },
    {
      "affs": [
        16
      ],
      "name": "Benedikt Jacobs"
    },
    {
      "affs": [
        4,
        17
      ],
      "name": "Mirle Schemionek",
      "orcid": "0000-0002-5947-3529"
    },
    {
      "affs": [
        1,
        2,
        18
      ],
      "name": "Francis Impens"
    },
    {
      "affs": [
        16
      ],
      "name": "Heiko Bruns"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Klaus-Peter Knobeloch",
      "orcid": "0000-0003-1587-1944"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/eha3e5gq0jxrg.bib",
  "cited_by": 1,
  "doi": "10.1038/s41375-026-03086-y",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13713586/",
  "id": "eha3e5gq0jxrg",
  "issns": [
    "0887-6924",
    "1476-5551"
  ],
  "landing_url": "https://doi.org/10.1038/s41375-026-03086-y",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Ubiquitin and proteasome pathways"
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  "openalex": "W7202175841",
  "pdf_url": "https://www.nature.com/articles/s41375-026-03086-y.pdf",
  "pmcid": "PMC13713586",
  "pmid": "42581242",
  "published": "2026-08-11",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/eha3e5gq0jxrg.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:24:06Z",
      "native_id": "PMC13713586",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41375-026-03086-y"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Ubiquitin and proteasome pathways",
      "subfield": "molecular-biology"
    }
  ],
  "title": "USP8 controls proteostasis pathways in B cells and multiple myeloma",
  "title_text": "USP8 controls proteostasis pathways in B cells and multiple myeloma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:14Z",
  "url": "https://research.draconitic.com/paper/eha3e5gq0jxrg",
  "venue": "Leukemia",
  "versions": []
}