USP8 Controls Proteostasis Pathways in B Cells and Multiple Myeloma
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Ubiquitin-specific protease 8 (USP8) is a multifunctional deubiquitinating enzyme that plays a pivotal role in the regulation of endosomal and lysosomal trafficking. Several studies showed that USP8 is critically involved in the pathogenesis of various tumor entities. Recently, USP8 emerged as a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we have comprehensively analyzed mice with deletion of Usp8 at different stages of B-cell development. Furthermore, we evaluated the function of USP8 in proteasome inhibition susceptible and Bortezomib (BTZ) resistant patient derived MM cells using depletion of USP8 and treatment with DUB-IN-2, a widely used inhibitor published to target USP8. Usp8 depletion in Usp8 f/f C d19 -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, indicating proteotoxic stress. Moreover, we identified these modifications as preferred substrates of USP8. In MM cells, efficient USP8 knockdown reduced survival by inducing lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ. Our results highlight the potential of targeting USP8 and the combination of DUB-IN-2 and BTZ in treating BTZ-resistant MM. However, our biochemical and cellular analyses raise fundamental concerns about the function of DUB-IN-2 as a USP8 inhibitor.
Authors 14
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Almut Dufner corresponding
Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
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Ghent University · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Department of Biomolecular Medicine, 9052 Gent, Belgium
VIB-UGent Center for Medical Biotechnology, 9052 Gent, Belgium
VIB-UGent Center for Medical Biotechnology, 905 Gent, Belgium
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Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
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Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 7910 Freiburg, Germany
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University of Freiburg · Leiden University Medical Center
Affiliation as printed
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
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Leiden University Medical Center · Max Planck Institute for Biology of Ageing
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany
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University of Freiburg · Max Planck Institute for Biology of Ageing
Affiliation as printed
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany
Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 796 Freiburg, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 7106 Freiburg, Germany
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University of Freiburg · Leiden University Medical Center
Affiliation as printed
Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79106 Freiburg, Germany
Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 796 Freiburg, Germany
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 7106 Freiburg, Germany
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University of Freiburg · Leiden University Medical Center · University Medical Center Freiburg
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, 79110 Freiburg, Germany
Faculty of Biology, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 7106 Freiburg, Germany
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University of Freiburg · University of Cologne · University Medical Center Freiburg · Helmholtz Munich · Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases · Max Planck Institute for Biology of Ageing · Institut für Immunologie · Ludwig-Maximilians-Universität München
Affiliation as printed
Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, 79110 Freiburg, Germany
Faculty of Biology, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79106 Freiburg, Germany
CECAD - Cluster of Excellence, University of Cologne, 50931 Cologne, Germany
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany
Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, 81377 Munich, Germany
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Ghent University · Universitätsklinikum Aachen · VIB-UGent Center for Medical Biotechnology · RWTH Aachen University
Affiliation as printed
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation University Hospital RWTH Aachen, Germany
Department of Biomolecular Medicine, 9052 Gent, Belgium
VIB Proteomics Core, 9052 Gent, Belgium
VIB-UGent Center for Medical Biotechnology, 905 Gent, Belgium
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University of Freiburg · Friedrich-Alexander-Universität Erlangen-Nürnberg · Ghent University · Universitätsklinikum Erlangen · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Department of Biomolecular Medicine, 9052 Gent, Belgium
VIB Proteomics Core, 9052 Gent, Belgium
VIB-UGent Center for Medical Biotechnology, 9052 Gent, Belgium
Department of Internal Medicine 5, Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 7106 Freiburg, Germany
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University of Freiburg · Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Department of Internal Medicine 5, Hematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 7906 Freiburg, Germany
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 7106 Freiburg, Germany
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