Multiple myeloma, gammopathies

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

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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

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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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Supplementary Information accompanies this paper on the Leukemia website

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