Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration.

Zhangrong Cheng, Weikang Gan, Qian Xiang, Kangcheng Zhao, Haiyang Gao, Yuhang Chen, Pengzhi Shi, Anran Zhang, Gaocai Li, Yu Song, Xiaobo Feng, Cao Yang, Yukun Zhang

Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. · pubmed

Paper

Abstract

Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper claims that impaired degradation of PLCG1 by chaperone-mediated autophagy leads to cellular senescence and intervertebral disc degeneration. This research addresses a mechanism related to cellular senescence, which is a key factor in the aging process and age-related degeneration, making it relevant to longevity research.

Author of this paper? Send a correction.