CRL2APPBP2-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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外文摘要：Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by in-dividually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into hMSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated de-gradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn down-regulates one of the canonical aging marker-P21wan/cip1,and thereby delays senescence.Our work provides important insights into how CRL2APPBP2-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

外文关键词：

Cullinsstem cellsenescenceagingproteostasisubiquitinationAPPBP2TSPYL2

作者：

Daoyuan Huang、Qian Zhao、Kuan Yang、Jinghui Lei、Ying Jing、Hongyu Li、Chen Zhang、Shuai Ma、Shuhui Sun、Yusheng Cai、Guibin Wang、Jing Qu、Weiqi Zhang、Si Wang、Guang-Hui Liu

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作者单位：

Advanced Innovation Center for Human Brain Protection,National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China

Aging Translational Medicine Center,International Center for Aging and Cancer,Beijing Municipal Geriatric Medical Research Center,Xuanwu Hospital,Capital Medical University,Beijing 100053,China

University of Chinese Academy of Sciences,Beijing 100049,China

CAS Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics and China National Center for Bioinformation,Chinese Academy of Sciences,Beijing 100101,China

Sino-Danish College,University of Chinese Academy of Sciences,Beijing,101408,China

National Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China

The Fifth People's Hospital of Chongqing,Chongqing 400062,China

State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China

Beijing Institute for Stem Cell and Regenerative Medicine,Beijing,100101,China

Institute for Stem Cell and Regeneration,CAS,Beijing 100101,China

State Key Laboratory of Proteomics,Beijing Proteome Research Center,National Center for Protein Sciences(Beijing),Beijing Institute of Lifeomics,Beijing 102206,China

State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China

University of Chinese Academy o

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基金：

国家重点研发计划国家重点研发计划国家重点研发计划国家重点研发计划STI2030-Major ProjectsSTI2030-Major Projects国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金中国科学院战略规划重点项目CAS Project for Young Scientists in Basic ResearchCAS Project for Young Scientists in Basic ResearchProgram of the Beijing Natural Science FoundationFellowship of China Postdoctoral Science FoundationProject for Technology Development of Beijingaffiliated Medical Research InstitutesPilot Project for Public Welfare Development and Reform of Beijingaffiliated Medical Research Institutes中国科学院青年创新促进会项目中国科学院青年创新促进会项目中国科学院青年创新促进会项目Young Elite Scientists Sponsorship Program by CASTYoung Elite Scientists Sponsorship Program by CASTInformatization Plan of Chinese Academy of SciencesInformatization Plan of Chinese Academy of SciencesInformatization Plan of Chinese Academy of SciencesNew Cornerstone Science Foundation through the XPLORER PRIZE(2021-1045)Excellent Young Talents Program of Capital Medical UniversityExcellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher TeamBeijing Hospitals Authority Youth Programme

项目编号：

2020YFA08040002022YFA11037002020YFA01122002021YFF12010002021ZD02024002022YFA110380082201714819210068212501192149301921682019194920992049304920491163212100182192863821220248XDA16000000YSBR-076YSBR-012Z1900192022M71221611000023T00000203631011000022T000000461062E1CAZW040120220832023092YESS20200012YESS20210002CAS-WX2021SF-0301CAS-WX2022SDC-XK14CAS-WX2021SF-010112300927BPHR202203105QML20230806

出版年：

2024

DOI：

10.1007/s11427-023-2451-3

中国科学:生命科学(英文版)

中国科学院

中国科学:生命科学(英文版)

CSTPCD

影响因子：0.806

ISSN：1674-7305

年,卷(期)：2024.67(3)

参考文献量69