1.兰州大学第二临床医学院,兰州 730000
2.兰州大学第二医院康复医学科,兰州 730000
Received:09 November 2024,
Revised:2025-01-03,
Accepted:09 January 2025,
Published:28 April 2026
移动端阅览
者静甜,李晓玲.泛素化和去泛素化在多发性硬化发病机制中的作用[J].重庆医科大学学报,2026,51(04):529-535.
Zhe Jingtian,Li Xiaoling.The role of ubiquitination and deubiquitination in the pathogenesis of multiple sclerosis[J].Journal of Chongqing Medical University,2026,51(04):529-535.
者静甜,李晓玲.泛素化和去泛素化在多发性硬化发病机制中的作用[J].重庆医科大学学报,2026,51(04):529-535. DOI: 10.13406/j.cnki.cyxb.003760.
Zhe Jingtian,Li Xiaoling.The role of ubiquitination and deubiquitination in the pathogenesis of multiple sclerosis[J].Journal of Chongqing Medical University,2026,51(04):529-535. DOI: 10.13406/j.cnki.cyxb.003760.
多发性硬化(multiple sclerosis,MS)是一种慢性、免疫介导的中枢神经系统(central nervous system,CNS)炎症性脱髓鞘疾病,其发病原因尚不明确,仍是具有挑战性和致残性的疾病,因而会对家庭和社会造成极大的负担。现在越来越多研究表明,泛素化和去泛素化在MS神经炎症反应、免疫功能调节、髓鞘形成和修复中起着关键作用。泛素化和去泛素化是重要的蛋白质翻译后修饰方式,泛素化是泛素分子对靶蛋白进行特异性修饰的过程,不仅调节蛋白质的降解,还调控蛋白质的功能和定位;去泛素化是泛素分子从靶蛋白上移除的过程,对泛素化有着平衡作用。二者之间的动态平衡在MS发病中发挥着重要作用。本文将结合最新的研究进展,介绍泛素化酶和去泛素化酶(deubiquitination enzymes,DUBs)在MS发病机制的生物学作用及潜在的分子机制,探索MS潜在的治疗靶点。
Multiple sclerosis(MS) is a chronic,immune-mediated inflammatory demyelinating disease of the central nervous system. With an unknown pathogenesis,MS remains a challenging and disabling condition that imposes a significant burden on families and society. Increasing evidence suggests that ubiquitination and deubiquitination are of pivotal significance in the neuroinflammatory responses,modulation of immune functions,as well as the formation and repair of myelin in MS. Ubiquitination and deubiquitination represent crucial post-translational modifications of proteins. Ubiquitination entails the specific modification of target proteins by ubiquitin molecules,which not only governs protein degradation but also orchestrates the functionality and localization of proteins. Conversely,deubiquitination is the process through which ubiquitin molecules are detached from target proteins,which serves as a counterbalance to ubiquitination. The dynamic balance between these two processes plays a pivotal role in MS pathogenesis. This article integrates the latest research advancements to elucidate the biological roles and underlying molecular mechanisms of ubiquitinating enzymes and deubiquitinating enzymes in the pathogenesis of MS,with the aim of uncovering potential therapeutic targets for this challenging disease.
McGinley MP , Goldschmidt CH , Rae-Grant AD . Diagnosis and treatment of multiple sclerosis:a review [J ] . JAMA , 2021 , 325 ( 8 ): 765 - 779 .
Eshaghi A , Young AL , Wijeratne PA , et al . Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data [J ] . Nat Commun , 2021 , 12 ( 1 ): 2078 .
Dobson R , Giovannoni G . Multiple sclerosis-a review [J ] . Euro J Neurology , 2019 , 26 ( 1 ): 27 - 40 .
de la Maza SS , Maurino J , Borges M , et al . Measuring productivity loss in early relapsing-remitting multiple sclerosis [J ] . Mult Scler Relat Disord , 2022 , 58 : 103398 .
Thompson AJ , Baranzini SE , Geurts J , et al . Multiple sclerosis [J ] . Lancet , 2018 , 391 ( 10130 ): 1622 - 1636 .
Kwon YT , Ciechanover A . The ubiquitin code in the ubiquitin-proteasome system and autophagy [J ] . Trends Biochem Sci , 2017 , 42 ( 11 ): 873 - 886 .
贾凤菊 , 傅 琳 , 焦倩 , 等 . 泛素连接酶和去泛素化酶在帕金森病中的作用 [J ] . 生物化学与生物物理进展 , 2023 , 50 ( 4 ): 795 - 807 .
Jia FJ , Fu L , Jiao Q , et al . Roles of ubiquitin ligases and deubiquitylases in Parkinson’s disease [J ] . Prog Biochem Biophys , 2023 , 50 ( 4 ): 795 - 807 .
Goto J , Otaki Y , Watanabe T , et al . The role of HECT-type E3 ligase in the development of cardiac disease [J ] . Int J Mol Sci , 2021 , 22 ( 11 ): 6065 .
Toma-Fukai S , Shimizu T . Structural diversity of ubiquitin E3 ligase [J ] . Molecules , 2021 , 26 ( 21 ): 6682 .
Clague MJ , Urbé S , Komander D . Breaking the chains:deubiquitylating enzyme specificity begets function [J ] . Nat Rev Mol Cell Biol , 2019 , 20 ( 6 ): 338 - 352 .
Lange SM , Armstrong LA , Kulathu Y . Deubiquitinases:From mechanisms to their inhibition by small molecules [J ] . Mol Cell , 2022 , 82 ( 1 ): 15 - 29 .
Snyder NA , Silva GM . Deubiquitinating enzymes (DUBs):regulation,homeostasis,and oxidative stress response [J ] . J Biol Chem , 2021 , 297 ( 3 ): 101077 .
Luo WX , Zhang GR , Wang ZQ , et al . Ubiquitin-specific proteases:Vital regulatory molecules in bone and bone-related diseases [J ] . Int Immunopharmacol , 2023 , 118 : 110075 .
Hwang JT , Lee A , Kho C . Ubiquitin and ubiquitin-like proteins in cancer,neurodegenerative disorders,and heart diseases [J ] . Int J Mol Sci , 2022 , 23 ( 9 ): 5053 .
Parihar N , Bhatt LK . Deubiquitylating enzymes:potential target in autoimmune diseases [J ] . Inflammopharmacology , 2021 , 29 ( 6 ): 1683 - 1699 .
Do HA , Baek KH . Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases [J ] . Ageing Res Rev , 2021 , 69 : 101367 .
Yadav D , Lee JY , Puranik N , et al . Modulating the ubiquitin-proteasome system:a therapeutic strategy for autoimmune diseases [J ] . Cells , 2022 , 11 ( 7 ): 1093 .
Guan H , Mao LK , Wang JF , et al . Exosomal RNF157 mRNA from prostate cancer cells contributes to M2 macrophage polarization through destabilizing HDAC1 [J ] . Front Oncol , 2022 , 12 : 1021270 .
Qi TT , Jing RH , Ma B , et al . The E3 ligase RNF157 inhibits lens epithelial cell apoptosis by negatively regulating p53 in age-related cataracts [J ] . Invest Ophthalmol Vis Sci , 2022 , 63 ( 4 ): 11 .
Wang P , Zhao JJ , Tan YK , et al . RNF157 attenuates CD4 + T cell-mediated autoimmune response by promoting HDAC1 ubiquitination and deg radation [J ] . Theranostics , 2023 , 13 ( 11 ): 3509 - 3523 .
Wang YF , Wang HY . The emerging role of histone deacetylase 1 in allergic diseases [J ] . Front Immunol , 2022 , 13 : 1027403 .
Tang R , Langdon WY , Zhang J . Regulation of immune responses by E3 ubiquitin ligase Cbl-b [J ] . Cell Immunol , 2019 , 340 : 103878 .
Jafari D , Mousavi MJ , Keshavarz Shahbaz S , et al . E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy [J ] . Clin Exp Immunol , 2021 , 204 ( 1 ): 14 - 31 .
Peer S , Cappellano G , Hermann-Kleiter N , et al . Regulation of lymphatic GM-CSF expression by the E3 ubiquitin ligase cbl-b [J ] . Front Immunol , 2018 , 9 : 2311 .
Martin SJ , Brand-Arzamendi K , Saab G , et al . GM-CSF is a marker of compartmentalised intrathecal inflammation in multiple sclerosis [J ] . Mult Scler , 2023 , 29 ( 11/12 ): 1373 - 1382 .
Cho JJ , Xu ZW , Parthasarathy U , et al . Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation [J ] . Nat Commun , 2019 , 10 ( 1 ): 701 .
Eriksson AM , Leikfoss IS , Abrahamsen G , et al . Exploring the role of the multiple sclerosis susceptibility gene CLEC16A in T cells [J ] . Scand J Immunol , 2021 , 94 ( 1 ): e13050 .
Pearson G , Chai BX , Vozheiko T , et al . Clec16a,Nrdp1,and USP8 form a ubiquitin-dependent tripartite complex that regulates β-cell mitophagy [J ] . Diabetes , 2018 , 67 ( 2 ): 265 - 277 .
Hain HS , Pandey R , Bakay M , et al . Inducible knockout of Clec16a in mice results in sensory neurodegeneration [J ] . Sci Rep , 2021 , 11 ( 1 ): 9319 .
Passemard S , Perez F , Gressens P , et al . Endoplasmic reticulum and Golgi stress in microcephaly [J ] . Cell Stress , 2019 , 3 ( 12 ): 369 - 384 .
Langston SP , Grossman S , England D , et al . Discovery of TAK-981,a first-in-class inhibitor of SUMO-activating enzyme for the treatment of cancer [J ] . J Med Chem , 2021 , 64 ( 5 ): 2501 - 2520 .
Kim KW , Ljunggren-Rose Å , Matta P , et al . Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation:Novel approach toward treatment of inflammatory CNS demyelinating disease [J ] . J Neuroimmunol , 2023 , 384 : 578219 .
Zhu WY , Krishna S , Garcia C , et al . Daam2 driven degradation of VHL promotes gliomagenesis [J ] . Elife , 2017 , 6 : e31926 .
Ding XY , Jo J , Wang CY , et al . The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation [J ] . Genes Dev , 2020 , 34 ( 17/18 ): 1177 - 1189 .
Niu JQ , Yu GD , Wang XR , et al . Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation [J ] . Neuron , 2021 , 109 ( 19 ): 3104 - 3118 .
Sardar D , Deneen B . Rnf43 is “lord of the ring” finger proteins in remyelination [J ] . Neuron , 2021 , 109 ( 19 ): 3069 - 3071 .
Ma PC , Mao BY . The many faces of the E3 ubiquitin ligase,RNF220,in neural development and beyond [J ] . Dev Growth Differ , 2022 , 64 ( 2 ): 98 - 105 .
Li YW , Wan LP , Song NN , et al . RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination [J ] . Sci Adv , 2024 , 10 ( 6 ): eadk3931 .
Kim J , Choi TI , Park S , et al . Rnf220 cooperates with Zc4h2 to specify spinal progenitor domains [J ] . Development , 2018 , 145 ( 17 ): dev165340 .
Ma PC , Song NN , Cheng XN , et al . ZC 4 H 2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling [J ] . J Mol Cell Biol , 2020 , 12 ( 5 ): 337 - 344 .
Song NN , Ma PC , Zhang Q , et al . Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development [J ] . Development , 2020 , 147 ( 6 ): dev185199 .
Mevissen TET , Komander D . Mechanisms of deubiquitinase specificity and regulation [J ] . Annu Rev Biochem , 2017 , 86 : 159 - 192 .
Zhang Y , Liu RB , Cao Q , et al . USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance [J ] . J Clin Invest , 2019 , 129 ( 7 ): 2856 - 2871 .
Wang KK , Yang ZH , Sarkis G , et al . Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration,neurotrauma and neuro-injuries [J ] . Expert Opin Ther Targets , 2017 , 21 ( 6 ): 627 - 638 .
Graham SH , Liu H . Life and death in the trash heap:the ubiquitin proteasome pathway and UCHL1 in brain aging,neurodegenerative disease and cerebral ischemia [J ] . Ageing Res Rev , 2017 , 34 : 30 - 38 .
Liu H , Povysheva N , Rose ME , et al . Role of UCHL1 in axonal injury and functional recovery after cerebral ischemia [J ] . Proc Natl Acad Sci USA , 2019 , 116 ( 10 ): 4643 - 4650 .
Górska E , Tylicka M , Hermanowicz A , et al . UCHL1,besides leptin and fibronectin,also could be a sensitive marker of the relapsing-remitting type of multiple sclerosis [J ] . Sci Rep , 2023 , 13 ( 1 ): 3423 .
Mi ZP , Graham SH . Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury [J ] . Ageing Res Rev , 2023 , 86 : 101856 .
Kumar D , Ambasta RK , Kumar P . Ubiquitin biology in neurodegenerative disorders:from impairment to therapeutic strategies [J ] . Ageing Res Rev , 2020 , 61 : 101078 .
Johann L , Soldati S , Müller K , et al . A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS [J ] . J Clin Invest , 2023 , 133 ( 24 ): e168314 .
Voet S , Guire CM , Hagemeyer N , et al . A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation [J ] . Nat Commun , 2018 , 9 ( 1 ): 2036 .
Montarolo F , Perga S , Tessarolo C , et al . TNFAIP3 deficiency affects monocytes,monocytes-derived cells and microglia in mice [J ] . Int J Mol Sci , 2020 , 21 ( 8 ): 2830 .
Pasupala N , Morrow ME , Que LT , et al . OTUB1 non-catalytically stabilizes the E2 ubiquitin-conjugating enzyme UBE2E1 by preventing its autoubiquitination [J ] . J Biol Chem , 2018 , 293 ( 47 ): 18285 - 18295 .
Wang X , Mulas F , Yi WJ , et al . OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes [J ] . EMBO J , 2019 , 38 ( 10 ): e100947
Zhou XF , Yu JY , Cheng XH , et al . The deubiquitinase Otub1 controls the activation of CD8 + T cells and NK cells by regulating IL-15-mediated priming [J ] . Nat Immunol , 2019 , 20 ( 7 ): 879 - 889 .
Dagar G , Kumar R , Yadav KK , et al . Ubiquitination and deubiquitination:implications on cancer therapy [J ] . Biochim Biophys Acta Gene Regul Mech , 2023 , 1866 ( 4 ): 194979 .
Kim K , Pröbstel AK , Baumann R , et al . Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis [J ] . Brain , 2021 , 144 ( 2 ): 450 - 461 .
Soucy TA , Smith PG , Milhollen MA , et al . An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer [J ] . Nature , 2009 , 458 ( 7239 ): 732 - 736 .
Banerjee S , Ji CG , Mayfield JE , et al . Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2 [J ] . Proc Natl Acad Sci USA , 2018 , 115 ( 32 ): 8155 - 8160 .
Amiri Z , Jalili S , Tarahomi M , et al . Curcumin’s spice-infused therapeutic promise:disease severity alleviation in a mouse model of multiple sclerosis via modulation of immune responses [J ] . Mol Biol Rep , 2023 , 50 ( 11 ): 8843 - 8853 .
0
Views
0
下载量
0
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution
京公网安备11010802024621
