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Dufner, A.* ; Thery, F.* ; Monaco, G.* ; Lazarevic, J.* ; Gorka, O.* ; Chevalier, N.* ; Alonso, M.C.* ; Frosch, M.* ; Noort, G.J.v.d.H.v.* ; Allmeroth, K.* ; Prinz, M.* ; Groß, O.* ; Ovaa, H.* ; Geurink, P.P.* ; Schamel, W.W.* ; Denzel, M.S.* ; Heissmeyer, V. ; Jacobs, B.* ; Schemionek, M.* ; Impens, F.* ; Bruns, H.* ; Knobeloch, K.*

USP8 controls proteostasis pathways in B cells and multiple myeloma.

Leukemia, DOI: 10.1038/s41375-026-03086-y (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene Knockdown ; Proteasome Inhibitor ; Proteasome ; Ubiquitin ; Proteostasis ; Bortezomib ; Germinal Center ; Mg132 ; Multiple Myeloma ; Hek 293 Cells; Ubiquitin; Death; Nedd8; Neddylation; Activation; Inhibitors; Lineage; Cancer; Enzyme; Malt1
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Publisher Springer
Publishing Place The Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Research Unit Molecular Immune Regulation (AMIR)
Grants Deutsche Krebshilfe (German Cancer Aid)
Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
Deutsche Forschungsgemeinschaft (German Research Foundation)