HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here we described the role of this HSP90 form, referred to as oncogenic HSP90, in the regulation of cytosolic metabolic pathways in proliferating B-cell lymphoma cells. Oncogenic HSP90 assisted in the organization of metabolic enzymes into non-membrane–bound functional compartments. Under experimental conditions that conserved cellular proteostasis, oncogenic HSP90 coordinated and sustained multiple metabolic pathways required for energy production and maintenance of cellular biomass as well as for secretion of extracellular metabolites. Conversely, inhibition of oncogenic HSP90, in absence of apparent client protein degradation, decreased the efficiency of MYC-driven metabolic reprogramming. This study reveals that oncogenic HSP90 supports metabolism in B-cell lymphoma cells and patients with diffuse large B-cell lymphoma, providing a novel mechanism of activity for HSP90 inhibitors. Significance: The oncogenic form of HSP90 organizes and maintains functional multienzymatic metabolic hubs in cancer cells, suggesting the potential of repurposing oncogenic HSP90 selective inhibitors to disrupt metabolism in lymphoma cells.

中文翻译：

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致癌 HSP90 促进侵袭性 B 细胞淋巴瘤的代谢改变

HSP90 对于维持细胞蛋白质稳态至关重要。在癌细胞中，HSP90 也成为稳定多蛋白复合物（包括信号通路和转录复合物）的成核位点。在这里，我们描述了这种 HSP90 形式（称为致癌 HSP90）在增殖 B 细胞淋巴瘤细胞中胞质代谢途径调节中的作用。致癌 HSP90 协助将代谢酶组织成非膜结合的功能区室。在保存细胞蛋白质稳态的实验条件下，致癌 HSP90 协调和维持能量产生和细胞生物量维持以及细胞外代谢物分泌所需的多种代谢途径。相反，抑制致癌 HSP90，在没有明显的客户蛋白降解的情况下，降低了 MYC 驱动的代谢重编程的效率。这项研究表明，致癌 HSP90 支持 B 细胞淋巴瘤细胞和弥漫性大 B 细胞淋巴瘤患者的代谢，为 HSP90 抑制剂提供了一种新的活性机制。意义：HSP90 的致癌形式在癌细胞中组织和维持功能性多酶代谢中枢，表明重新利用致癌 HSP90 选择性抑制剂破坏淋巴瘤细胞代谢的潜力。