Related Experiment Video
Updated: Aug 13, 2026
09:47
Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
Published on: May 10, 2022
USP8 controls proteostasis pathways in B cells and multiple myeloma
Almut Dufner1, Fabien Thery2,3, Gianni Monaco4,5
1Institute of Neuropathology, Medical Center-University of Freiburg/Medical Faculty - University of Freiburg, Freiburg, Germany. almut.dufner@uniklinik-freiburg.de.
Leukemia
|August 11, 2026
Summary
Targeting Ubiquitin-specific protease 8 (USP8) impacts B-cell development and multiple myeloma (MM) cell survival. USP8 inhibition combined with Bortezomib (BTZ) shows promise for treating BTZ-resistant MM.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Ubiquitin-specific protease 8 (USP8) is crucial for endosomal-lysosomal trafficking and implicated in tumor pathogenesis.
- USP8 is identified as a vulnerability gene in multiple myeloma (MM), suggesting its importance in B-cell and plasma cell biology.
Purpose of the Study:
- To investigate the role of USP8 in B-cell development and its function in Bortezomib (BTZ)-sensitive and -resistant multiple myeloma (MM) cells.
- To evaluate USP8 depletion and the USP8 inhibitor DUB-IN-2 as therapeutic strategies for MM.
Main Methods:
- Stage-specific Usp8 deletion in mice during B-cell development.
- USP8 depletion and treatment with DUB-IN-2 in patient-derived MM cells (BTZ-sensitive and -resistant).
- Biochemical analysis to assess USP8 inhibitor function and protein ubiquitination.
Main Results:
- Usp8 deletion in mice altered B-cell survival and development, favoring immature B cells and affecting germinal center and plasma cells.
- Cells with inactive USP8 accumulated mixed ubiquitin/NEDD8 chains, indicating proteotoxic stress and identifying USP8 substrates.
- USP8 knockdown in MM cells reduced survival through lysosomal dysfunction.
- DUB-IN-2 treatment enhanced ER stress in response to BTZ, challenging its role as a specific USP8 inhibitor.
Conclusions:
- USP8 plays a significant role in B-cell development and MM cell survival, impacting lysosomal function and proteotoxic stress.
- Targeting USP8 presents therapeutic potential for multiple myeloma.
- The combination of DUB-IN-2 and BTZ emerges as a potential novel strategy for treating Bortezomib-resistant MM.
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