转录因子 EB (TFEB) 是溶酶体生物合成和自噬的主要调节因子。我们确定了 TFEB 的一个独特的核相互作用组，其中泛素特异性蛋白酶 7 (USP7) 成为 TFEB 的关键翻译后调节剂。 USP7 的基因耗尽和抑制揭示了其在保持核和细胞质区室中 TFEB 稳定性方面的关键作用。具体而言，USP7 被鉴定为负责去除 TFEB 赖氨酸残基 K116、K264 和 K274 处 K48 连接的多聚泛素化信号的去泛素化酶，从而防止其蛋白酶体降解。功能测定表明，USP7 参与保护 TFEB 介导的营养剥夺转录反应，同时还调节自噬流和溶酶体生物发生。由于 USP7 是一种去泛素酶，可保护 TFEB 免遭蛋白酶体降解，因此这些发现为在 TFEB 失调和代谢异常的情况下（特别是某些癌症）靶向 USP7-TFEB 轴的治疗奠定了基础。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with ubiquitin-specific protease 7 (USP7) emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.