UCHL1 alleviates nucleus pulposus cell senescence by promoting chaperone-mediated autophagy antagonizing autophagy-dependent ferroptosis through deubiquitination of HSPA8.

Zhouwei Wu, Shu Yang, Zhichen Jiang, Yuxuan Zhu, Haibo Liang, Yifeng Shi, Sunlong Li, Shuhao Zhang, Yining Xu, Chenglong Hong, Juntao Ying, Chenggui Wang, Xiangyang Wang

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. · pubmed

Paper

Abstract

Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its "KFERQ" motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering

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Research summary

UCHL1 mitigates nucleus pulposus cell senescence by activating chaperone-mediated autophagy. The study addresses a mechanism related to cellular senescence and intervertebral disc degeneration, which are important aspects of aging and age-related degeneration.

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