USP8 controls proteostasis pathways in B cells and multiple myeloma

Dufner A, Thery F, Monaco G, Lazarevic J, Gorka O, Chevalier N, Campos Alonso M, Frosch M, van der Heden van Noort GJ, Allmeroth K, Prinz M, Groß O, Ovaa H, Geurink PP, Schamel WW, Denzel MS, Heissmeyer V, Jacobs B, Schemionek M, Impens F, Bruns H, Knobeloch KP (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Leukemia Springer Nature

DOI: 10.1038/s41375-026-03086-y

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. (Figure presented.)

Authors with CRIS profile

Benedikt Jacobs Department of Medicine 5 – Haematology and Oncology Heiko Bruns Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) BE Belgium (BE) Leiden University Medical Center NL Netherlands (NL) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Universitätsklinikum Aachen (UKA) DE Germany (DE) Max-Planck-Institut für Biologie des Alterns / Max Planck Institute for Biology of Ageing DE Germany (DE)

How to cite

APA:

Dufner, A., Thery, F., Monaco, G., Lazarevic, J., Gorka, O., Chevalier, N.,... Knobeloch, K.P. (2026). USP8 controls proteostasis pathways in B cells and multiple myeloma. Leukemia. https://doi.org/10.1038/s41375-026-03086-y

MLA:

Dufner, Almut, et al. "USP8 controls proteostasis pathways in B cells and multiple myeloma." Leukemia (2026).

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