Technion Integrated Cancer Center (TICC), The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
Technion Integrated Cancer Center (TICC), The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
Biochem Biophys Res Commun. 2019 Sep 17;517(2):188-192. doi: 10.1016/j.bbrc.2019.07.040. Epub 2019 Jul 18.
The endoplasmic reticulum (ER) is a major site for protein synthesis, folding and transport, lipid and steroid synthesis, regulating redox potential, as well as calcium storage. It therefore relies on delicate homeostasis, and perturbation of the ER function and induction of ER stress can lead to apoptosis. One cause of disruption of the ER homeostasis is the accumulation of misfolded proteins. To prevent this perturbation, the Endoplasmic Reticulum-Associated Degradation (ERAD) quality control machinery is recruited to remove these proteins in a three-step process: (1) extraction from the ER, (2) ubiquitination, and (3) subsequent proteasomal degradation. However, the identity of the proteins regulated by the proteasome following induction of the ER stress has remained obscure. In the present study, we investigated the role of the proteasome in the modulation of the proteome of HeLa cells after treatment with thapsigargin and tunicamycin, two drugs known to induce ER stress through accumulation of misfolded proteins. Using label-free quantitative proteomics we found that out of the proteins identified to decrease in their level following induction of ER stress, more than 64% are targeted by the proteasome. Among these proteins, key players of the Wnt signaling pathway, such as β-catenin and GSK3, as well as α-catenin which is involved in cell-cell adhesion, were identified as being modulated by the proteasome upon ER stress.
内质网（ER）是蛋白质合成、折叠和运输、脂质和类固醇合成、调节氧化还原电位以及钙储存的主要场所。因此，它依赖于精细的动态平衡，内质网功能的紊乱和内质网应激的诱导会导致细胞凋亡。内质网平衡破坏的一个原因是错误折叠蛋白质的积累。为了防止这种干扰，内质网相关降解（ERAD）质量控制机制被招募来通过三步过程去除这些蛋白质：（1）从 ER 中提取，（2）泛素化，和（3）随后的蛋白酶体降解。然而，在诱导内质网应激后，由蛋白酶体调节的蛋白质的身份仍然不清楚。在本研究中，我们研究了蛋白酶体在 HeLa 细胞用 thapsigargin 和 tunicamycin 处理后蛋白质组调节中的作用，这两种药物通过错误折叠蛋白质的积累已知会诱导内质网应激。使用无标记定量蛋白质组学，我们发现，在诱导内质网应激后，蛋白质水平下降的蛋白质中，超过 64%的蛋白质是由蛋白酶体靶向的。在这些蛋白质中，Wnt 信号通路的关键参与者，如β-catenin 和 GSK3，以及参与细胞间黏附的α-catenin，被鉴定为在 ER 应激时被蛋白酶体调节。
