泛素蛋白酶体途径（UPP）是蛋白质降解的主要途径，也是哺乳动物细胞中的关键调节机制。 UPP 抑制剂，包括 E1 泛素激活酶的一流抑制剂 TAK-243，目前正在使用和测试用于治疗一系列疾病，特别是癌症。在此，我们揭示 TAK-243 对一系列培养的哺乳动物细胞（αT3、HeLa 和 SH-SY5Y）中的 Ca2 处理具有重大影响。对激动剂诱导的 Ca2 动员、基础细胞质 Ca2 水平、内质网 (ER) 的 Ca2 泄漏、钙库操纵的 Ca2 进入和线粒体 Ca2 摄取都有影响。这些影响与内质网应激的诱导相关，并且大多数似乎是由内质网钙渗漏增强所支撑的。总体而言，这些数据表明 TAK-243 重新编程了哺乳动物细胞的 Ca2 处理特性，并且当使用 UPP 抑制剂作为治疗剂时应考虑这些影响。版权所有 © 2023。由 Elsevier B.V. 出版。

The ubiquitin-proteasome pathway (UPP) is a major route for protein degradation and a key regulatory mechanism in mammalian cells. UPP inhibitors, including TAK-243, a first-in-class inhibitor of the E1 ubiquitin-activating enzyme, are currently being used and tested for treatment of a range of diseases, particularly cancer. Here, we reveal that TAK-243 has major effects on Ca2+ handling in a range of cultured mammalian cells (αT3, HeLa and SH-SY5Y). Effects were seen on agonist-induced Ca2+ mobilization, basal cytosolic Ca2+ levels, Ca2+ leak from the endoplasmic reticulum (ER), store-operated Ca2+ entry and mitochondrial Ca2+ uptake. These effects correlated with induction of ER stress, and most seemed to be underpinned by enhanced Ca2+ leak from the ER. Overall, these data indicate that TAK-243 reprograms the Ca2+-handling properties of mammalian cells and that these effects should be considered when UPP inhibitors are employed as therapeutic agents.Copyright © 2023. Published by Elsevier B.V.