CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence  

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 

机构地区：[1]Advanced Innovation Centerfor Human Brain Protection,National Clinical Research Centerfor Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China [2]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [3]Aging Translational MedicineCenter,International Centerfor Aging and Cancer,Bejing Municipal GeriatricMedical Research Center,Xuanwu Hospital,Capital Medical University,Beijing 100053,China [4]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [5]University of Chinese Academy of Sciences,Beijing 100049,China [6]Beijing Institute for Stem Cell and Regenerative Medicine,Beijing,100101,China [7]CAS Key Laboratory of Genomic and Precision Medicine,Bejing Institute of Genomics and China National Center for Bioinformation,Chinese Academy of Sciences,Beijing 100101,China [8]Institute for Stem Cell and Regeneration,CAS,Beijing 100101,China [9]The Fifth People's Hospital of Chongqing,Chongqing 400062,China [10]Sino-Danish Cllege,University of Chinese Academy of Sciences,Beijing,101408,China [11]National Laboratory of Biomacromolecules,CAS Center for Excelence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China [12]State Key Laboratory of Proteomics,Beijing Proteome Research Center,National Center for Protein Sciences(Beijing),Beijing Institute of Lifeomics,Beijing 102206,China

出　　处：《Science China(Life Sciences)》2024年第3期460-474,共15页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2020YFA0804000,2022YFA1103700,2020YFA0112200,2021YFF1201000,the STI2030-Major Projects-2021ZD0202400,2022YFA1103800);the National Natural Science Foundation of China(82201714,81921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,32000500,82271600,82001477,82201727);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000);CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012);the Program of the Beijing Natural Science Foundation(Z190019);the Fellowship of China Postdoctoral Science Foundation(2022M712216);the Project for Technology Development of Beijing-affiliated Medical Research Institutes(11000023T000002036310);the Pilot Project for Public Welfare Development and Reform of Beijing-affiliated Medical Research Institutes(11000022T000000461062);Youth Innovation Promotion Association of CAS(E1CAZW0401,2022083,2023092);Young Elite Scientists Sponsorship Program by CAST(YESS20200012,YESS20210002);the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CAS-WX2022SDC-XK14,CASWX2021SF-0101);New Cornerstone Science Foundation through the XPLORER PRIZE(2021-1045);Excellent Young Talents Program of Capital Medical University(12300927);Excellent Young Talents Training Program for the Construction of Beijing Municipal University Teacher Team(BPHR202203105);Beijing Hospitals Authority Youth Programme(QML20230806)。

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 individually 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 h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关 键 词：Cullins stem cell SENESCENCE AGING PROTEOSTASIS UBIQUITINATION APPBP2 TSPYL2 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]