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.

中文翻译：

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14-3-3ζ结合蛋白酶体，限制蛋白水解功能并增强对蛋白酶体抑制剂的敏感性。

14-3-3蛋白是细胞内信号转导的主要调节子家族，但它们对蛋白酶体功能的影响尚不清楚。我们证明14-3-3ζ结合11S蛋白酶体激活剂，限制了蛋白酶体组装和细胞降解蛋白质的能力。为了确定14-3-3ζ蛋白酶体结合在骨髓瘤细胞中的功能影响，进行沉默和过表达实验。我们发现14-3-3ζ的下调会损害骨髓瘤细胞的生长，并赋予对临床使用的蛋白酶体抑制剂的抗性。在一大批新诊断的骨髓瘤患者中，14-3-3ζ表达升高与高危骨髓瘤遗传亚型和总体预后较差有关。我们的工作证明了14-3-3ζ在调节蛋白酶体功能，骨髓瘤细胞生长和对治疗药物的敏感性方面的重要作用，