USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK

化学 脱氮酶 嵌合体(遗传学) 安普克 细胞生物学 生物化学 泛素 基因 蛋白激酶A 生物
作者
Jing Liu,Xiaoping Hu,Kaixiu Luo,Yan Xiong,Li Chen,Zhen Wang,Hiroyuki Inuzuka,C. D. Qian,Xufen Yu,Ling Xie,Adil Muneer,Dingpeng Zhang,João A. Paulo,Xian Chen,Jian Jin,Wenyi Wei
出处
期刊:Journal of the American Chemical Society [American Chemical Society]
标识
DOI:10.1021/jacs.4c02373
摘要

Deubiquitinase-targeting chimeras (DUBTACs) have been recently developed to stabilize proteins of interest, which is in contrast to targeted protein degradation (TPD) approaches that degrade disease-causing proteins. However, to date, only the OTUB1 deubiquitinase has been utilized to develop DUBTACs via an OTUB1 covalent ligand, which could unexpectedly compromise the endogenous function of OTUB1 owing to its covalent nature. Here, we show for the first time that deubiquitinase USP7 can be harnessed for DUBTAC development. Based on a noncovalent ligand of USP7, we developed USP7-based DUBTACs that stabilized the ΔF508-CFTR mutant protein as effectively as the previously reported OTUB1-based DUBTAC. Importantly, using two different noncovalent ligands of USP7, we developed the first AMPK DUBTACs that appear to selectively stabilize different isoforms of AMPKβ, leading to elevated AMPK signaling. Overall, these results highlight that, in addition to OTUB1, USP7 can be leveraged to develop DUBTACs, thus significantly expanding the limited toolbox for targeted protein stabilization and the development of novel AMPK DUBTACs as potential therapeutics.
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