The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma

Alexander Vdovin, Tomas Jelinek, David Zihala, Tereza Sevcikova, Michal Durech, Hana Sahinbegovic, Renata Snaurova, Dhwani Radhakrishnan, Marcello Turi, Zuzana Chyra, Tereza Popkova, Ondrej Venglar, Matous Hrdinka, Roman Hajek and Michal Simicek ()
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Alexander Vdovin: University of Ostrava
Tomas Jelinek: University of Ostrava
David Zihala: University of Ostrava
Tereza Sevcikova: University of Ostrava
Michal Durech: University of Ostrava
Hana Sahinbegovic: University of Ostrava
Renata Snaurova: University of Ostrava
Dhwani Radhakrishnan: University of Ostrava
Marcello Turi: University of Ostrava
Zuzana Chyra: University of Ostrava
Tereza Popkova: University of Ostrava
Ondrej Venglar: University of Ostrava
Matous Hrdinka: University of Ostrava
Roman Hajek: University of Ostrava
Michal Simicek: University of Ostrava

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.

Date: 2022
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DOI: 10.1038/s41467-022-34654-2

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