• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

伴侣蛋白介导的自噬对PLCG1的降解受损会促进细胞衰老和椎间盘退变。

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

作者信息

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

机构信息

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

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

出版信息

Autophagy. 2025 Feb;21(2):352-373. doi: 10.1080/15548627.2024.2395797. Epub 2024 Sep 10.

DOI:10.1080/15548627.2024.2395797
PMID:39212196
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11759519/
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 or knockdown of . Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value. ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NHCl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.

摘要

伴侣介导的自噬（CMA）缺陷与细胞衰老相关，但其机制仍知之甚少。在此，我们发现CMA抑制以钙依赖的方式诱导细胞衰老，并确定了其在肿瘤坏死因子（TNF）诱导的髓核细胞（NPC）衰老和椎间盘退变中的作用。基于结构和功能蛋白质组学筛选，磷脂酶Cγ1（PLCG1）被预测为CMA缺陷影响钙稳态的潜在底物。我们进一步证实PLCG1是CMA调节细胞内钙通量的关键介质。CMA阻断导致的PLCG1异常积累导致钙超载，从而诱导NPC衰老。对人体标本的免疫分析表明，CMA的限速蛋白LAMP2A减少或PLCG1增加与椎间盘衰老相关，并且大鼠中TNF诱导的椎间盘退变可通过过表达或敲低来抑制。由于CMA失调、钙超载和细胞衰老是椎间盘退变和其他与年龄相关的退行性疾病的共同特征，发现能够连接这些扰动的可操作分子靶点可能具有治疗价值。全反式维甲酸（ATRA）；溴脱氧尿苷（BrdU）；细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A/p21）；细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A/p16-INK4A）；伴侣介导的自噬（CMA）；椎间盘高度指数（DHI）；内质网（ER）；免疫沉淀（IP）；肌醇1,4,5-三磷酸（IP3）；肌醇1,4,5-三磷酸受体（ITPR/IP3R）；椎间盘（IVD）；椎间盘退变（IVDD）；敲低（KD）；敲除（KO）；亮抑酶肽（Leu）；磁共振成像（MRI）；质谱（MS）；氯化铵和亮抑酶肽（N/L）；髓核（NP）；髓核细胞（NPC）；蛋白酶抑制剂（PI）；磷脂酶C（PLC）；磷脂酶Cγ1（PLCG1）；活性氧（ROS）；实时定量逆转录PCR（RT-qPCR）；衰老相关β-半乳糖苷酶（SA-GLB1/β-gal）；衰老相关分泌表型（SASP）；饥饿（STV）；串联质量标签（TMT）；肿瘤坏死因子（TNF）；肿瘤蛋白p53（TP53）；泛素-蛋白酶体系统（UPS）

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/f7c5d446d3f8/KAUP_A_2395797_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/81bcf41f5162/KAUP_A_2395797_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/ab55ea46f6b9/KAUP_A_2395797_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/9d3655747eff/KAUP_A_2395797_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/b2ef6141afbb/KAUP_A_2395797_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/901cd12a97d0/KAUP_A_2395797_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/594011d82ad3/KAUP_A_2395797_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/7abdfd502ab1/KAUP_A_2395797_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/f7c5d446d3f8/KAUP_A_2395797_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/81bcf41f5162/KAUP_A_2395797_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/ab55ea46f6b9/KAUP_A_2395797_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/9d3655747eff/KAUP_A_2395797_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/b2ef6141afbb/KAUP_A_2395797_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/901cd12a97d0/KAUP_A_2395797_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/594011d82ad3/KAUP_A_2395797_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/7abdfd502ab1/KAUP_A_2395797_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e4f/11759519/f7c5d446d3f8/KAUP_A_2395797_F0008_C.jpg

相似文献

1
Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration.伴侣蛋白介导的自噬对PLCG1的降解受损会促进细胞衰老和椎间盘退变。
Autophagy. 2025 Feb;21(2):352-373. doi: 10.1080/15548627.2024.2395797. Epub 2024 Sep 10.
2
Autophagy regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration.自噬通过在黏液瘤样二尖瓣退变中经由SQSTM1/p62介导的选择性自噬调节CDKN1A/p21和CDKN2A/p16的降解，从而调控细胞衰老。
Autophagy. 2025 Mar 4:1-23. doi: 10.1080/15548627.2025.2469315.
3
Restoration of lysosomal function attenuates autophagic flux impairment in nucleus pulposus cells and protects against mechanical overloading-induced intervertebral disc degeneration.溶酶体功能的恢复可减轻髓核细胞自噬流损伤，并预防机械过载诱导的椎间盘退变。
Autophagy. 2025 May;21(5):979-995. doi: 10.1080/15548627.2024.2440844. Epub 2024 Dec 25.
4
METTL3 Promotes Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration by Regulating TLR2 m6A Methylation and Gut Microbiota.METTL3 通过调控 TLR2 m6A 甲基化和肠道微生物群促进椎间盘退变中髓核细胞衰老。
J Gerontol A Biol Sci Med Sci. 2024 Aug 1;79(8). doi: 10.1093/gerona/glae150.
5
Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration.伴侣蛋白介导的自噬通过双重机制来平衡过早衰老和衰老细胞溶解，以预防椎间盘退变。
Bone Res. 2025 Jun 12;13(1):62. doi: 10.1038/s41413-025-00441-0.
6
ASIC1a Promotes nucleus pulposus derived stem cells apoptosis through modulation of SIRT3-dependent mitochondrial redox homeostasis in intervertebral disc degeneration.ASIC1a通过调节椎间盘退变中依赖SIRT3的线粒体氧化还原稳态促进髓核来源干细胞凋亡。
Redox Rep. 2025 Dec;30(1):2504120. doi: 10.1080/13510002.2025.2504120. Epub 2025 Jul 8.
7
The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn trafficking.NLRX1-SLC39A7 复合物通过调节线粒体锌转运来协调线粒体动力学和线粒体自噬，从而使椎间盘年轻化。
Autophagy. 2024 Apr;20(4):809-829. doi: 10.1080/15548627.2023.2274205. Epub 2023 Nov 3.
8
Mechanistic Interactions Driving Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration: A Multi-Axial Perspective of Mechanical, Immune, and Metabolic Pathways.驱动椎间盘退变中髓核细胞衰老的机制性相互作用：机械、免疫和代谢途径的多轴视角
JOR Spine. 2025 Jul 2;8(3):e70089. doi: 10.1002/jsp2.70089. eCollection 2025 Sep.
9
Risk factors for progression of nucleus pulposus degeneration in the lumbar intervertebral disc: a retrospective analysis using the disc signal intensity index.腰椎间盘髓核退变进展的危险因素：一项使用椎间盘信号强度指数的回顾性分析
Spine J. 2025 Jul;25(7):1466-1473. doi: 10.1016/j.spinee.2025.01.036. Epub 2025 Feb 1.
10
RTA 408 attenuates TBHP-Induced apoptosis in nucleus pulposus cells via Nrf2/ARE and NF-κB signaling pathways: in vitro and in vivo evidence for mitigating rats' intervertebral disc degeneration.RTA 408通过Nrf2/ARE和NF-κB信号通路减轻叔丁基过氧化氢诱导的髓核细胞凋亡：减轻大鼠椎间盘退变的体内外证据
Arthritis Res Ther. 2025 Jun 19;27(1):128. doi: 10.1186/s13075-025-03588-7.

引用本文的文献

1
Pure platelet-rich plasma delays intervertebral disc degeneration by activating SIRT1-mediated autophagy in nucleus pulposus cells.纯富血小板血浆通过激活髓核细胞中SIRT1介导的自噬来延缓椎间盘退变。
J Orthop Surg Res. 2025 Aug 22;20(1):786. doi: 10.1186/s13018-025-06205-0.
2
Cellular senescence and other age-related mechanisms in skeletal diseases.骨骼疾病中的细胞衰老及其他与年龄相关的机制。
Bone Res. 2025 Jul 7;13(1):68. doi: 10.1038/s41413-025-00448-7.
3
Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration.

本文引用的文献

1
Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-κB/NLRP3 pathway.缺乏伴侣蛋白介导的自噬通过调节 p300/NF-κB/NLRP3 通路促进 LPS 诱导的小胶质细胞活化。
Sci Adv. 2023 Oct 6;9(40):eadi8343. doi: 10.1126/sciadv.adi8343.
2
The lysosomal proteome of senescent cells contributes to the senescence secretome.衰老细胞的溶酶体蛋白质组有助于衰老分泌组。
Aging Cell. 2022 Oct;21(10):e13707. doi: 10.1111/acel.13707. Epub 2022 Sep 10.
3
Cellular senescence and senolytics: the path to the clinic.
伴侣蛋白介导的自噬通过双重机制来平衡过早衰老和衰老细胞溶解，以预防椎间盘退变。
Bone Res. 2025 Jun 12;13(1):62. doi: 10.1038/s41413-025-00441-0.
4
Exosomes derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by alleviating the senescence of nucleus pulposus cells through epigenetic modifications.源自暴露于缺氧和炎症环境的间充质干细胞的外泌体，通过表观遗传修饰减轻髓核细胞衰老，从而减缓椎间盘退变。
Bioact Mater. 2025 Mar 20;49:515-530. doi: 10.1016/j.bioactmat.2025.02.046. eCollection 2025 Jul.
5
Lipid metabolic disorders and their impact on cartilage endplate and nucleus pulposus function in intervertebral disk degeneration.脂质代谢紊乱及其对椎间盘退变中软骨终板和髓核功能的影响。
Front Nutr. 2025 Mar 10;12:1533264. doi: 10.3389/fnut.2025.1533264. eCollection 2025.
6
Fine-Tuned Expression of Evolutionarily Conserved Signaling Molecules in the Notochord.脊索中进化保守信号分子的微调表达
Int J Mol Sci. 2024 Dec 20;25(24):13631. doi: 10.3390/ijms252413631.
细胞衰老与衰老细胞清除：通往临床的道路。
Nat Med. 2022 Aug;28(8):1556-1568. doi: 10.1038/s41591-022-01923-y. Epub 2022 Aug 11.
4
Exogenous Klotho ameliorates extracellular matrix degradation and angiogenesis in intervertebral disc degeneration via inhibition of the Rac1/PAK1/MMP-2 signaling axis.外源性 Klotho 通过抑制 Rac1/PAK1/MMP-2 信号轴改善椎间盘退变中外细胞外基质降解和血管生成。
Mech Ageing Dev. 2022 Oct;207:111715. doi: 10.1016/j.mad.2022.111715. Epub 2022 Aug 8.
5
Cellular senescence: the good, the bad and the unknown.细胞衰老：好的、坏的和未知的。
Nat Rev Nephrol. 2022 Oct;18(10):611-627. doi: 10.1038/s41581-022-00601-z. Epub 2022 Aug 3.
6
Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration.靶向维甲酸受体 α-辅阻遏物相互作用激活伴侣介导的自噬并保护视网膜免受变性。
Nat Commun. 2022 Jul 21;13(1):4220. doi: 10.1038/s41467-022-31869-1.
7
Chaperone-mediated autophagy protects against atherosclerosis.伴侣蛋白介导的自噬可预防动脉粥样硬化。
Autophagy. 2022 Oct;18(10):2505-2507. doi: 10.1080/15548627.2022.2096397. Epub 2022 Jul 19.
8
Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration.PIEZO1 引发的 NF-κB 和 periostin 自我扩增环加速了机械诱导的椎间盘细胞衰老和椎间盘退变。
Mol Ther. 2022 Oct 5;30(10):3241-3256. doi: 10.1016/j.ymthe.2022.05.021. Epub 2022 May 26.
9
Chaperone-mediated autophagy degrades Keap1 and promotes Nrf2-mediated antioxidative response.伴侣蛋白介导的自噬降解 Keap1 并促进 Nrf2 介导的抗氧化反应。
Aging Cell. 2022 Jun;21(6):e13616. doi: 10.1111/acel.13616. Epub 2022 May 10.
10
Protective role of chaperone-mediated autophagy against atherosclerosis.伴侣介导的自噬对动脉粥样硬化的保护作用。
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2121133119. doi: 10.1073/pnas.2121133119. Epub 2022 Apr 1.