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

• DOI: 10.1038/s41467-022-34654-2
• Publication Date: 2022-11-10T22:03:19Z
• Authors: 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; Michal Simicek
• Keywords: Deubiquitinating enzyme

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 survival, while amount of intracellular has strong predictive effect. Focused CRISPR screen, transcriptional proteomic analysis identify deubiquitinase OTUD1 as critical mediator synthesis, proteasome inhibitor sensitivity tumor burden in MM. Mechanistically, deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates production which coincides accumulation unfolded proteins higher ER stress. The elevated load on ultimately potentiates response to inhibitors providing window rational therapy. Collectively, our findings support significance machinery biomarker target combinatory treatment patients.