USP7 protects TFEB from proteasome-mediated degradation

The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with 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.

转录因子EB（transcription factor EB, TFEB）是溶酶体生物发生与自噬的核心调控因子。本研究鉴定得到TFEB独特的核相互作用组，其中泛素特异性蛋白酶7（USP7）被确立为TFEB的关键翻译后调控因子。对USP7进行基因敲除与抑制实验证实，其在维持细胞核与细胞质区域内TFEB稳定性方面发挥至关重要的作用。具体而言，USP7作为去泛素化酶，可在赖氨酸残基K116、K264与K274位点去除TFEB上的K48连接型多聚泛素化信号，从而阻止其被蛋白酶体降解。功能实验结果表明，USP7可参与维持TFEB介导的营养匮乏应答转录调控程序，同时还可调节自噬流与溶酶体生物发生过程。鉴于USP7作为去泛素化酶能够保护TFEB免于蛋白酶体降解，本研究发现为针对TFEB失调与代谢异常相关疾病（尤其是部分癌症）中的USP7-TFEB轴开展治疗性靶向研究提供了理论依据。