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SUMO化修饰作为关键的蛋白质翻译后修饰，在神经退行性疾病的病理进程中发挥重要作用。朊病毒病是一类由朊蛋白错误折叠引起的致死性神经退行性疾病，其发病机制尚未完全阐明。本研究以朊病毒感染的SMB-S15细胞模型及139A/ME7毒株感染的小鼠模型为研究对象，系统探讨了SUMO化修饰在朊病毒病进程中的动态变化及其与朊蛋白的相互作用机制。通过Western blot、免疫荧光和免疫组化分析发现，朊病毒感染终末期小鼠脑组织及SMB-S15细胞中SUMO1修饰蛋白水平显著降低，而SUMO1的mRNA表达水平却呈现升高趋势。免疫共沉淀实验证实，朊蛋白与SUMO1存在相互作用，且病毒感染后二者的结合显著增强。同时，在不同感染阶段的小鼠脑组织中，SUMO1修饰蛋白水平在朊病毒感染后不同时间点呈先下降，再上升，再下降的趋势。本研究首次揭示朊病毒感染可导致SUMO1修饰蛋白失衡，SUMO1与朊蛋白的异常相互作用可能在朊病毒病的发病机制中发挥关键作用，为深入理解朊病毒病的分子机制提供了新的实验依据和治疗靶点。
Abstract：SUMOylation, as a key protein post-translational modification, plays an important role in the pathological process of neurodegenerative diseases. Prion diseases are a class of fatal neurodegenerative diseases caused by pron misfolding, and their pathogenesis has not been fully elucidated. In this study, the SMB-S15 cell model of prion infection and the mouse model of 139A/ME7 strain infection were used as the research objects, and the dynamic changes of SUMOylation modification in the process of prion disease and its interaction mechanism with prion proteins were systematically discussed. Western blot, immunofluorescence and immunohistochemistry analysis showed that the level of SUMO1 modified protein in the brain tissue and SMB-S15 cells of end-stage prion infection was significantly reduced, while the mRNA expression level of SUMO1 showed an increasing trend. Co-immunoprecipitation(Co-IP) assays confirmed that prion proteins had specific interactions with SUMO1, and the binding between the two was significantly enhanced after viral infection. At mean time, the level of SUMO1-modified protein in mouse brain tissue at different stages of infection showed a trend of decreasing first, then rising, and then decreasing at different time points after prion infection. The level of SUMO1-modified protein decreased progressively. This study revealed for the first time that prion infection can lead to imbalance of SUMO1-modifying proteins and disorders of SUMO1-modifying system, and the abnormal interaction between SUMO1 and prion proteins may play a key role in the pathogenesis of prion diseases, providing a new experimental basis and therapeutic target for in-depth understanding of the molecular mechanism of prion diseases.
[1]Vaquer-Alicea J,Diamond MI.Propagation of protein aggregation in neurodegenerative diseases[J].Annu Rev Biochem,2019,88:785-810.DOI:10.1146/annurev-biochem-061516-045049.
[2]Prusiner SB.Prions[J].Proc Natl Acad Sci U S A,1998,95(23):13363-13383.DOI:10.1073/pnas.95.23.13363.
[3]Prusiner SB.Novel proteinaceous infectious particles cause scrapie[J].Science,1982,216(4542):136-144.DOI:10.1126/science.6801762.
[4]王琳，杨微，姚强，等.香草酸对朊病毒感染细胞Pr PSc沉积抑制和细胞保护作用研究[J].病毒学报，2022,38(04):896-904.DOI:10.13242/j.cnki.bingduxuebao.004162.
[5]周冬花，武月章，王远，等.朊病毒感染的仓鼠脑组织中NLRP3介导的炎症反应机制的初步探索[J].病毒学报，2024,40(01):38-44.DOI:10.13242/j.cnki.bingduxuebao.004455.
[6]Flotho A,Melchior F.Sumoylation:a regulatory protein modification in health and disease[J].Annu Rev Biochem,2013,82:357-385.DOI:10.1146/annurev-biochem-061909-093311.
[7]Anderson DB,Zanella CA,Henley JM,et al.Sumoylation:implications for neurodegenerative diseases[J].Adv Exp Med Biol,2017,963:261-281.DOI:10.1007/978-3-319-50044-7_16.
[8]Wilkinson KA,Henley JM.Mechanisms,regulation and consequences of protein SUMOylation[J].Biochem J,2010,428(2):133-145.DOI:10.1042/bj20100158.
[9]Luo HB,Xia YY,Shu XJ,et al.SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination[J].Proc Natl Acad Sci U S A,2014,111(46):16586-16591.DOI:10.1073/pnas.1417548111.
[10]周冬花，王晶，肖康，等.SMB-S15细胞中朊病毒PMCA方法的建立及对白藜芦醇抗朊病毒作用的评价[J].病毒学报，2019,35(02):183-188.DOI:10.13242/j.cnki.bingduxuebao.003526.
[11]Krumova P,Weishaupt JH.Sumoylation in neurodegenerative diseases[J].Cell Mol Life Sci,2013,70(12):2123-2138.DOI:10.1007/s00018-012-1158-3.
[12]Guo C,Hildick KL,Luo J,et al.SENP3-mediated de SUMOylation of dynamin-related protein 1 promotes cell death following ischaemia[J].EMBO J,2013,32(11):1514-1528.DOI:10.1038/emboj.2013.65.
[13]Drisaldi B,Colnaghi L,Fioriti L,et al.SUMOylation is an inhibitory constraint that regulates the prion-like aggregation and activity of CPEB3[J].Cell Rep,2015,11(11):1694-1702.DOI:10.1016/j.celrep.2015.04.061.
[14]Kachemov M,Vaibhav V,Smith C,et al.Dysregulation of protein SUMOylation networks in Huntington’s disease R6/2 mouse striatum[J].Brain,2025,148(4):1212-1227.DOI:10.1093/brain/awae319.
[15]Huang CH,Yang TT,Lin KI.Mechanisms and functions of SUMOylation in health and disease:a review focusing on immune cells[J].J Biomed Sci,2024,31(1):16.DOI:10.1186/s12929-024-01003-y.
[16]Verma DK,Ghosh A,Ruggiero L,et al.The SUMO conjugase Ubc9 protects dopaminergic cells from cytotoxicity and enhances the stability of α-synuclein in Parkinson’s disease models[J].e Neuro,2020,7(5):ENEURO.0134-20.2020.DOI:10.1523/ENEURO.0134-20.2020.
[17]Steffan JS,Agrawal N,Pallos J,et al.SUMO modification of huntingtin and Huntington’s disease pathology[J].Science,2004,304(5667):100-104.DOI:10.1126/science.1092194.
[18]Chen DD,Shi Q,Liu X,et al.Aberrant SENP1-SUMO-Sirt3 signaling causes the disturbances of mitochondrial deacetylation and oxidative phosphorylation in prion-infected animal and cell models[J].ACS Chem Neurosci,2023,14(9):1610-1621.DOI:10.1021/acschemneuro.2c00786.
基本信息:
DOI：10.13242/j.cnki.bingduxuebao.250139
中图分类号:R373
引用信息:
[1]李纯洁,张卫卫,高利萍,等.朊病毒感染的细胞及小鼠模型中SUMO1修饰的变化及与朊蛋白相互作用的研究[J].病毒学报,2025,41(05):1376-1384.DOI:10.13242/j.cnki.bingduxuebao.250139.
基金信息:
传染病溯源预警与智能决策全国重点实验室（项目号：2024NITFID804），题目：实时震荡诱导蛋白扩增技术的应用研究; 中国疾病预防控制中心青年基金（项目号：2024A104），题目：朊病毒持续感染复制与转化过程中形态变化的研究~~
2025-09-09
2025-09-09
2025-09-09