Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications.
Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications.
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DOI：
10.3390/ph16040616
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发表时间：
2023-04-19
期刊：
影响因子：
--
通讯作者：
Voellmy R
中科院分区：
文献类型：
--
作者：
Vilaboa N;Lopez JA;de Mesa M;Escudero-Duch C;Winfield N;Bayford M;Voellmy R
许多癌细胞，包括多发性骨髓瘤细胞，暴露于细胞毒性浓度的天然产物雷公藤红素和醉茄素A或IHSF系列的合成化合物导致荧光素酶报告蛋白变性。蛋白质组学分析的洗涤剂不溶性提取物馏分HeLa细胞显示，醉茄素A，IHSF 058和IHSF 115引起变性的915，722和991 5132检测细胞蛋白质，分别，其中440靶向所有三种化合物。Western印迹显示，这些蛋白质的重要部分，在某些情况下接近总蛋白量的一半，未折叠。观察到靶蛋白的相对不加选择的共价修饰; IHSF 058修饰了1178种不同的蛋白质。进一步说明诱导的蛋白质稳态危机的深度，这些蛋白质中只有13%可检测地聚集，并且聚集的蛋白质中有79%不是共价修饰的靶。许多蛋白质稳态网络组件被修改和/或发现在聚集体。由研究化合物引起的蛋白质稳态破坏可能比由蛋白酶体抑制剂介导的更深刻。这些化合物通过不同的机制起作用，可能不太容易产生抗性。多发性骨髓瘤细胞对化合物特别敏感。建议开发一种额外的破坏多发性骨髓瘤蛋白质沉积的治疗方法。
Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested.
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影响因子：
4.7
作者：
Behl T;Sharma A;Sharma L;Sehgal A;Zengin G;Brata R;Fratila O;Bungau S
通讯作者：
Bungau S
影响因子：
3.7
作者：
Cardona M;López JA;Serafín A;Rongvaux A;Inserte J;García-Dorado D;Flavell R;Llovera M;Cañas X;Vázquez J;Sanchis D
通讯作者：
Sanchis D
影响因子：
5.6
作者：
Chen SR;Dai Y;Zhao J;Lin L;Wang Y;Wang Y
通讯作者：
Wang Y
DOI：
10.1083/jcb.201709072
发表时间：
2018-01-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Klaips CL;Jayaraj GG;Hartl FU
通讯作者：
Hartl FU
影响因子：
4.4
作者：
Bonzon-Kulichenko, Elena;Garcia-Marques, Fernando;Vazquez, Jesus
通讯作者：
Vazquez, Jesus