Divergent Proteome Reactivity Influences Arm-Selective Activation of the Unfolded Protein Response by Pharmacological Endoplasmic Reticulum Proteostasis Regulators.
Divergent Proteome Reactivity Influences Arm-Selective Activation of the Unfolded Protein Response by Pharmacological Endoplasmic Reticulum Proteostasis Regulators.
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DOI：
10.1021/acschembio.3c00042
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发表时间：
2023-08-18
影响因子：
4
通讯作者：
Kelly, Jeffery W.
中科院分区：
文献类型：
--
作者：
Kline, Gabriel M.;Paxman, Ryan J.;Lin, Chung-Yon;Madrazo, Nicole;Yoon, Leonard;Grandjean, Julia M. D.;Lee, Kyunga;Nugroho, Karina;Powers, Evan T.;Wiseman, R. Luke;Kelly, Jeffery W.
未折叠蛋白反应（UPR）的活化转录因子6（ATF 6）臂的药理学活化已被证明可用于改善许多病因多样性疾病的细胞和小鼠模型中的蛋白质稳态缺陷。先前的高通量筛选工作将小分子AA 147鉴定为有效和选择性的ATF 6活化化合物，其通过涉及其2-氨基-对甲酚亚结构代谢活化的机制起作用，提供醌甲基化物，然后共价修饰内质网（ER）蛋白二硫键异构酶（PDI）的子集。在该筛选中鉴定的另一种化合物AA 132也含有2-氨基-对甲酚部分;然而，该化合物显示出较低的转录选择性，而是全局激活UPR的所有三个臂。在这里，我们表明，AA 132激活全球UPR信号通过机制类似于AA 147，涉及代谢活化和共价修饰的蛋白质，包括多个PDIs。化学蛋白质组学分析表明，AA 132共价修饰PDI的程度大于AA 147。然而，由AA 147标记的PDI的程度比由AA 132标记的PDI更快地接近平台。这些观察结果共同表明，AA 132可以获得更大的蛋白质库进行共价修饰，可能是因为其活化形式比活化的AA 147更不易于淬灭。换句话说，活化的AA 132的较低反应性允许其在细胞环境中持续更长时间并修饰更多的PDI。总的来说，这些结果表明，AA 132通过增加ER PDI的参与在全球范围内激活UPR。与此一致，降低AA 132的细胞浓度减少了PDI修饰并使得能够选择性地激活ATF 6。我们的研究结果突出了代谢活化亲电稳定性，ER蛋白质组反应性和ER蛋白质稳态调节剂的烯胺酮化学型观察到的转录反应之间的关系，使下一代ATF 6活化化合物的持续发展。
Pharmacological activation of the activating transcription factor 6 (ATF6) arm of the unfolded protein response (UPR) has proven useful for ameliorating proteostasis deficiencies in cellular and mouse models of numerous etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino-p-cresol substructure affording a quinone methide, which then covalently modifies a subset of endoplasmic reticulum (ER) protein disulfide isomerases (PDIs). Another compound identified in this screen, AA132, also contains a 2-amino-p-cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent modification of proteins including multiple PDIs. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. However, the extent of PDI labeling by AA147 approaches a plateau more rapidly than PDI labeling by AA132. These observations together suggest that AA132 can access a larger pool of proteins for covalent modification, possibly because its activated form is less susceptible to quenching than activated AA147. In other words, the lower reactivity of activated AA132 allows it to persist longer and modify more PDIs in the cellular environment. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and enables selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.
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影响因子：
29
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
通讯作者：
Papa FR
影响因子：
5.3
作者：
Higa, Arisa;Taouji, Said;Chevet, Eric
通讯作者：
Chevet, Eric
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.
影响因子：
5
作者：
D'Amico, Domenico;Biondi, Olivier;Charbonnier, Frederic
通讯作者：
Charbonnier, Frederic
肝脏 ATF6 通过过氧化物酶体增殖物激活受体 α 增加脂肪酸氧化，减轻小鼠肝脏脂肪变性
影响因子：
7.7
作者：
Chen, Xuqing;Zhang, Feifei;Li, Yu
通讯作者：
Li, Yu