Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins.
Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins.
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DOI：
10.7554/elife.37168
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发表时间：
2018-08-07
期刊：
影响因子：
7.7
通讯作者：
Kelly JW
中科院分区：
文献类型：
--
作者：
Paxman R;Plate L;Blackwood EA;Glembotski C;Powers ET;Wiseman RL;Kelly JW
药理学臂选择性未折叠蛋白反应（UPR）信号通路激活正在成为一种有前途的策略，以改善内质网（ER）蛋白稳态的不平衡，涉及各种疾病。小分子N-（2-羟基-5-甲基苯基）-3-苯基丙酰胺（147）先前被鉴定为优先激活UPR的ATF 6臂，促进ER蛋白质稳态网络的保护性重塑。在这里，我们表明，147依赖性ATF 6激活需要代谢氧化，形成一个亲电试剂，优先与ER蛋白反应。被147共价修饰的蛋白质包括已知调节ATF 6活化的蛋白质二硫键异构酶（PDI）。PDI的遗传缺失扰乱了ATF 6靶基因BiP的147依赖性诱导，这暗示了PDI的共价修饰在用147处理所提供的ATF 6的优先活化中。因此，147是通过涉及调节ATF 6活性的ER驻留蛋白的局部代谢活化和选择性共价修饰的机制优先活化ATF 6信号传导的前药。
Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. The small molecule N-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (147) was previously identified to preferentially activate the ATF6 arm of the UPR, promoting protective remodeling of the ER proteostasis network. Here we show that 147-dependent ATF6 activation requires metabolic oxidation to form an electrophile that preferentially reacts with ER proteins. Proteins covalently modified by 147 include protein disulfide isomerases (PDIs), known to regulate ATF6 activation. Genetic depletion of PDIs perturbs 147-dependent induction of the ATF6-target gene, BiP, implicating covalent modifications of PDIs in the preferential activation of ATF6 afforded by treatment with 147. Thus, 147 is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.