Chen Liu, Wang Xiaoping, Wang Yuchen, Yao Qingxin, Liu Yunyao, Zhu Yongcheng, Huang He, Yang Hedan, Yang Yin, He Yuan, Qiang Lei
State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Global Platform One Vision, WuXi AppTec, Shanghai, China.
Aging Cell. 2025 Jul;24(7):e70078. doi: 10.1111/acel.70078. Epub 2025 May 8.
Skin aging is a complex process driven by intrinsic genetic factors and extrinsic environmental influences. In this study, sequestosome1 (SQSTM1/p62) was identified as a key regulator of senescence, the senescence-associated secretory phenotype (SASP), and skin aging. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of ubiquitin-specific protease 7 (USP7) during senescence induction by orchestrating its degradation through specific binding interactions. In particular, the Tyr-67 residue within the PB1 domain or Gln-418 within the UBA domain of p62 forms a hydrogen bond with Ala-993 in the Ubl5 domain of USP7. Mutations in either Tyr-67 or Gln-418 of p62, or Ala-993 of USP7, resulted in the induction of cellular senescence, highlighting the critical role of these molecular interactions in the regulation of aging processes.
皮肤衰老是一个由内在遗传因素和外在环境影响驱动的复杂过程。在本研究中，聚集体结合蛋白1（SQSTM1/p62）被确定为衰老、衰老相关分泌表型（SASP）和皮肤衰老的关键调节因子。值得注意的是，在人类和小鼠的衰老细胞及衰老皮肤中，p62的表达均降低。研究发现，表皮中p62的耗竭与加速衰老和SASP的启动呈正相关。机制上，p62在衰老诱导过程中通过特异性结合相互作用协调泛素特异性蛋白酶7（USP7）的降解，从而抑制其积累。具体而言，p62的PB1结构域内的Tyr-67残基或UBA结构域内的Gln-418与USP7的Ubl5结构域中的Ala-993形成氢键。p62的Tyr-67或Gln-418，或USP7的Ala-993发生突变，均导致细胞衰老的诱导，突出了这些分子相互作用在衰老过程调控中的关键作用。
