Ubiquitin-specific protease 8 controls B-cell proteostasis and survival representing a target in multiple myeloma

Abstract

AbstractUbiquitin-specific protease 8 is involved in endosomal/lysosomal trafficking, exerts multiple cellular functions, and was identified as a vulnerability gene for multiple myeloma, a disease characterized by clonal expansion of malignant plasma cells in the bone marrow. Here we characterized USP8 function in B cells and multiple myeloma, and analyzed its impact on the global and ubiquitin-modified proteome.Usp8depletion inUsp8f/fCd19-Cre mice affected B-cell survival and development favoring immature and innate-like B cells, as well as germinal center and plasma cells. This effect was accompanied by elevated immune-responses and Roquin depletion. Moreover, low USP8 expression at diagnosis correlated with decreased survival of multiple myeloma patients. B cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains as hallmarks of proteotoxic stress, which we identified as favored USP8 substrates. Efficient USP8 knockdown reduced survival of multiple myeloma cells resistant to proteasome inhibition by bortezomib in a lysosomal dysfunction-dependent manner. Of note, the inhibitor DUB-IN-2 even more potently resensitized bortezomib-resistant multiple myeloma cells in an ER stress response-synergistic manner, and we confirmed applicability of DUB-IN-2/bortezomib combination treatment in a mouse transplantation model. Our analyses uncovered the potential of USP8 inhibition and of DUB-IN-2/bortezomib combination treatment in multiple myeloma.