Functional protein homeostasis is essential for the maintenance of normal cellular physiology, cell growth, and cell survival. Proteasome inhibition in cancer cells can disturb protein homeostasis in such a way that synthetic proteasome inhibitors like bortezomib may selectively kill myeloma cells. Solid cancer cells appear to respond less to bortezomib which may in part be due to a rescue mechanism of the unfolded protein response/endoplasmic reticulum stress mechanism which leads to a temporary shutdown of protein biosynthesis at the translational level. Here we show that proteasome inhibition by bortezomib may also interfere with general protein biosynthesis already at the stage of nucleolar ribosome biogenesis. Ultrastructural analysis revealed not only that bortezomib induces conspicuous changes in cytoplasmic morphology but also pronounced morphological changes of the nucleolar ultrastructure, associated with an accumulation of the transcription factor ATF4 at nucleolar sites. Stress-induced intra-nucleolar ATF4 accumulation was observed in cancer cells in a dose and time dependent manner and ultrastructural studies revealed that ATF4 is preferentially localized inside the dense fibrillar and granular component of nucleoli. Furthermore, bortezomib affected not only the number of nucleoli, but also the volume and distribution of nucleolar components. The localization of ATF4 in the granular component of nucleoli together with its association with nascent RNA transcripts in cells undergoing proteotoxic cell stress could suggest a new function for ATF4 in cell stress management.

中文翻译：

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蛋白酶体抑制后，应激诱导转录因子ATF4积累在特定的rRNA加工核仁区域。

功能性蛋白质稳态对于维持正常的细胞生理，细胞生长和细胞存活是必不可少的。癌细胞中蛋白酶体的抑制作用可以干扰蛋白质体内稳态，从而使合成的蛋白酶体抑制剂（如硼替佐米）可​​以选择性杀死骨髓瘤细胞。固体癌细胞似乎对硼替佐米的反应较少，这可能部分是由于未折叠的蛋白质反应/内质网应激机制的抢救机制导致了翻译水平蛋白质生物合成的暂时关闭。在这里，我们显示了硼替佐米对蛋白酶体的抑制作用也可能已经干扰了核仁核糖体生物发生的阶段，已经干扰了一般蛋白质的生物合成。超微结构分析不仅表明硼替佐米诱导了细胞质形态的显着变化，而且还引起了核仁超微结构的明显形态变化，这与转录因子ATF4在核仁部位的积累有关。在癌细胞中以剂量和时间依赖性的方式观察到了应力诱导的核仁内ATF4的积累，超微结构研究表明ATF4优先位于核仁的致密纤维状和颗粒状成分内。此外，硼替佐米不仅影响核仁数目，而且影响核仁成分的体积和分布。