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

Author

Listed:
  • Alexander Vdovin

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Tomas Jelinek

    (University of Ostrava
    University Hospital Ostrava)

  • David Zihala

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Tereza Sevcikova

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Michal Durech

    (University of Ostrava
    University Hospital Ostrava)

  • Hana Sahinbegovic

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Renata Snaurova

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Dhwani Radhakrishnan

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Marcello Turi

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Zuzana Chyra

    (University of Ostrava
    University Hospital Ostrava)

  • Tereza Popkova

    (University of Ostrava
    University Hospital Ostrava)

  • Ondrej Venglar

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

  • Matous Hrdinka

    (University of Ostrava
    University Hospital Ostrava)

  • Roman Hajek

    (University of Ostrava
    University Hospital Ostrava)

  • Michal Simicek

    (University of Ostrava
    University Hospital Ostrava
    University of Ostrava)

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.

Suggested Citation

  • Alexander Vdovin & Tomas Jelinek & David Zihala & Tereza Sevcikova & Michal Durech & Hana Sahinbegovic & Renata Snaurova & Dhwani Radhakrishnan & Marcello Turi & Zuzana Chyra & Tereza Popkova & Ondrej, 2022. "The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34654-2
    DOI: 10.1038/s41467-022-34654-2
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    References listed on IDEAS

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    1. Alboukadel Kassambara & Thierry Rème & Michel Jourdan & Thierry Fest & Dirk Hose & Karin Tarte & Bernard Klein, 2015. "GenomicScape: An Easy-to-Use Web Tool for Gene Expression Data Analysis. Application to Investigate the Molecular Events in the Differentiation of B Cells into Plasma Cells," PLOS Computational Biology, Public Library of Science, vol. 11(1), pages 1-10, January.
    2. Fan Yao & Zhicheng Zhou & Jongchan Kim & Qinglei Hang & Zhenna Xiao & Baochau N. Ton & Liang Chang & Na Liu & Liyong Zeng & Wenqi Wang & Yumeng Wang & Peijing Zhang & Xiaoyu Hu & Xiaohua Su & Han Lian, 2018. "SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    3. Zhengkui Zhang & Yao Fan & Feng Xie & Hang Zhou & Ke Jin & Li Shao & Wenhao Shi & Pengfei Fang & Bing Yang & Hans van Dam & Peter ten Dijke & Xiaofeng Zheng & Xiaohua Yan & Junling Jia & Min Zheng & J, 2017. "Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
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