Dai Fangyan, Lee Hyemin, Zhang Yilei, Zhuang Li, Yao Hui, Xi Yuanxin, Xiao Zhen-Dong, You M James, Li Wei, Su Xiaoping, Gan Boyi
Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3192-3197. doi: 10.1073/pnas.1619588114. Epub 2017 Mar 8.
The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to and promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.
内质网（ER）传统上通过激活未折叠蛋白反应（UPR）与代谢稳态相关联，UPR由多个转录调节级联反应调控。BRCA1相关蛋白1（BAP1）是一种具有去泛素化酶活性的肿瘤抑制因子，与基因表达的染色质调节有关。在这里，我们表明BAP1抑制由未解决的代谢应激诱导的细胞死亡。BAP1的这种促生存作用取决于其去泛素化活性，并与其抑制代谢应激诱导的UPR转录网络能力相关。BAP1抑制葡萄糖剥夺诱导的活性氧生成和ATP耗竭，这两个细胞事件导致内质网应激诱导的细胞死亡。与此一致，基因敲除小鼠对衣霉素诱导的肾损伤更敏感。从机制上来说，我们表明BAP1通过激活转录因子3（ATF3）和C/EBP同源蛋白（CHOP）来抑制代谢应激诱导的UPR和细胞死亡，并揭示BAP1与和启动子结合并抑制它们的转录。综上所述，我们的结果确立了BAP1在调节细胞对代谢应激的适应性方面以前未被认识的作用，并揭示了BAP1在内质网应激基因调控网络调节中的关键功能。我们的研究也可能为进一步理解BAP1在癌症中的功能提供新的概念框架。
