Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2.
Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2.
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DOI：
10.1021/acschembio.1c00810
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发表时间：
2021-12-17
影响因子：
4
通讯作者：
Wiseman RL
中科院分区：
文献类型：
--
作者：
Rosarda JD;Baron KR;Nutsch K;Kline GM;Stanton C;Kelly JW;Bollong MJ;Wiseman RL
谷氨酸的细胞外积累是包括缺血性中风和阿尔茨海默氏病在内的许多神经退行性疾病的病理标志。在高细胞外浓度下，谷氨酸通过促进氧化应激造成神经元损伤，从而导致细胞死亡。这引起了人们对开发药理学方法以减轻高水平谷氨酸引起的氧化毒性的浓厚兴趣。在这里，我们证明小分子蛋白质稳态调节剂 AA147 在神经元来源的细胞培养模型中可以防止谷氨酸诱导的细胞死亡。虽然最初是作为未折叠蛋白反应的激活转录因子 6 (ATF6) 臂的激活剂开发的，但这种 AA147 依赖性的针对谷氨酸毒性的保护作用主要是通过激活 NRF2 调节的氧化应激反应来介导的。我们证明，AA147 通过涉及反应性亲电试剂的代谢激活和 KEAP1 共价修饰的机制选择性地激活神经元衍生细胞中的 NRF2，该机制类似于 ATF6 的 AA147 依赖性激活。这些结果定义了 AA147 预防谷氨酸诱导的氧化毒性的潜力，并强调了代谢激活的蛋白质稳态调节剂（如 AA147）激活保护性 ATF6 和 NRF2 应激反应信号通路以减轻与多种神经系统疾病相关的氧化损伤的潜力。
The extracellular accumulation of glutamate is a pathologic hallmark of numerous neurodegenerative diseases including ischemic stroke and Alzheimer’s disease. At high extracellular concentrations, glutamate causes neuronal damage by promoting oxidative stress, which can lead to cellular death. This has led to significant interest in developing pharmacologic approaches to mitigate the oxidative toxicity caused by high levels of glutamate. Here, we show that the small molecule proteostasis regulator AA147 protects against glutamate-induced cell death in a neuronal-derived cell culture model. While originally developed as an activator of the activating transcription factor 6 (ATF6) arm of the unfolded protein response, this AA147-dependent protection against glutamate toxicity is primarily mediated through activation of the NRF2-regulated oxidative stress response. We demonstrate that AA147 activates NRF2 selectively in neuronal-derived cells through a mechanism involving metabolic activation to a reactive electrophile and covalent modification of KEAP1—a mechanism analogous to that involved in the AA147-dependent activation of ATF6. These results define the potential for AA147 to protect against glutamate-induced oxidative toxicity and highlight the potential for metabolically activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 stress-responsive signaling pathways to mitigate oxidative damage associated with diverse neurologic diseases.
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定义Cap'n'Collar转录因子NRF1，NRF2和NRF3的功能靶标。
DOI：
10.3390/antiox9101025
发表时间：
2020-10-21
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Ibrahim L;Mesgarzadeh J;Xu I;Powers ET;Wiseman RL;Bollong MJ
通讯作者：
Bollong MJ
影响因子：
14.8
作者：
Grandjean JMD;Madhavan A;Cech L;Seguinot BO;Paxman RJ;Smith E;Scampavia L;Powers ET;Cooley CB;Plate L;Spicer TP;Kelly JW;Wiseman RL
通讯作者：
Wiseman RL
影响因子：
16.2
作者：
ANKARCRONA, M;DYPBUKT, JM;NICOTERA, P
通讯作者：
NICOTERA, P
影响因子：
1.5
作者：
Adachi, Yusuke;Yamamoto, Keisuke;Mori, Kazutoshi
通讯作者：
Mori, Kazutoshi
DOI：
10.1073/pnas.2103196118
发表时间：
2021-09-28
影响因子：
11.1
作者：
Kroeger, Heike;Grandjean, Julia M. D.;Lin, Jonathan H.
通讯作者：
Lin, Jonathan H.