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Multiple myeloma, gammopathies

14-3-3ζ binds the proteasome, limits proteolytic function and enhances sensitivity to proteasome inhibitors

Leukemia volume 32, pages 744–751 (2018)Cite this article

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Abstract

14-3-3 proteins are a family of master regulators of intracellular signaling, yet their impact on proteasome function is unknown. We demonstrate that 14-3-3ζ binds the 11S proteasome activator, limiting proteasome assembly and cellular capacity for protein degradation. To define the functional impact of 14-3-3ζ proteasomal binding in myeloma cells, silencing and overexpression experiments are performed. We find that downregulation of 14-3-3ζ impairs myeloma cell growth and confers resistance to clinically used proteasome inhibitors. In a large cohort of newly diagnosed myeloma patients, elevated expression of 14-3-3ζ is associated with high risk myeloma genetic subtypes and worse prognosis overall. Our work demonstrates the important role of 14-3-3ζ in regulating proteasome function, myeloma cell growth and sensitivity to therapeutics, and suggests regulation of 14-3-3ζ as a new approach in myeloma therapy.

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Acknowledgements

This work is supported by the Richard and Annelly Deets Myeloma Foundation, and the Levine Family Foundation

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University, Atlanta, USA,

    Y Gu, C Torre, J Kaufman, A Nooka, L Bernal-Mizrachi, S-Y Sun, J Chen, L H Boise & S Lonial

  2. Winship Cancer Institute of Emory University, Atlanta, USA,

    Y Gu, M Rupji, J Arora, J Kaufman, A Nooka, L Bernal-Mizrachi, P Vertino, S-Y Sun, J Chen, H Fu, J Kowalski, L H Boise & S Lonial

  3. 4DGenome Inc, Atlanta, GA, USA

    K Xu

  4. Division of Medical Oncology, Dana Farber Cancer Institute, Boston, USA,

    M Samur & N Munshi

  5. Department of Radiation Oncology, Emory University, Atlanta, USA,

    B G Barwick & P Vertino

  6. Department of Medical Oncology and Hematology, Tom Baker Cancer Center, Calgary, Alberta, Canada

    P Neri

  7. Department of Biostatistics and Bioinformatics, RSPH, Emory University, Atlanta, USA,

    J Kowalski

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  1. Y Gu
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Corresponding author

Correspondence to S Lonial.

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Competing interests

SL is a consultant for Millennium, Onyx, Novartis, BMS, Janssen and Celgene, none of which is relevant for the current manuscript. The remaining authors declare no conflict of interest.

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Gu, Y., Xu, K., Torre, C. et al. 14-3-3ζ binds the proteasome, limits proteolytic function and enhances sensitivity to proteasome inhibitors. Leukemia 32, 744–751 (2018). https://doi.org/10.1038/leu.2017.288

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