泛素化修饰调控小胶质细胞功能参与神经系统疾病发生的研究进展

Research progress on ubiquitination-mediated regulation of microglial function in pathogenesis of neurological disorders

摘要

小胶质细胞是中枢神经系统中的固有免疫细胞，在免疫监视中起重要作用。泛素化修饰作为一种关键的翻译后修饰机制，与小胶质细胞的稳态维持、炎症反应和吞噬功能等密切相关，E3泛素连接酶和去泛素化酶可以通过多种方式调控小胶质细胞的功能，而小胶质细胞功能异常又影响多种神经系统疾病的发生发展。本文介绍泛素化修饰调控小胶质细胞功能的最新进展，总结相关信号通路，明确E3泛素连接酶和去泛素化酶在小胶质细胞功能调节中的靶点和机制，进一步探讨靶向泛素化修饰调控小胶质细胞功能治疗神经系统疾病的潜在作用。

Abstract

Microglia are innate immune cells of the central nervous system (CNS) that play a crucial role in immune surveillance. Ubiquitination, as a key post-translational modification mechanism, is closely involved in regulating microglial homeostasis, inflammatory responses, and phagocytic functions. E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) can modulate microglial function through multiple pathways, while microglial dysfunction contributes to the pathogenesis of various neurological disorders. This article reviews recent advances in ubiquitination-mediated regulation of microglial function, summarizes relevant signaling pathways, clarifies the targets and mechanisms of E3s and DUBs in microglial regulation, and further explores the potential therapeutic value of targeting the ubiquitination system to regulate microglial function for the treatment of neurological disorders.

关键词

小胶质细胞 / 神经系统疾病 / 泛素化 / E3泛素连接酶 / 去泛素化酶

Key words

Microglia / Neurological disorders / Ubiquitination / E3 ubiquitin ligase / Deubiquitinating enzymes

参考文献

[1] COLONNA M, BUTOVSKY O. Microglia function in the central nervous system during health and neurodegeneration[J]. Annu Rev Immunol, 2017, 35: 441-468.

[2] SIERRA A, MIRON V E, PAOLICELLI R C, et al. Microglia in health and diseases: Integrative hubs of the central nervous system (CNS)[J]. Cold Spring Harb Perspect Biol, 2024, 16(8): a041366.

[3] WANG S, PAN L, SUN C, et al. Balancing microglial density and activation in central nervous system development and disease[J]. Curr Issues Mol Biol, 2025, 47(5): 344.

[4] CAO J, YUAN J, LIU N, et al. Microglial dynamics and emerging therapeutic strategies in CNS homeostasis and pathology[J]. Front Pharmacol, 2025, 16: 1577809.

[5] GAO C, JIANG J, TAN Y, et al. Microglia in neurodegenerative diseases: Mechanism and potential therapeutic targets[J]. Signal Transduct Target Ther, 2023, 8(1): 359.

[6] GUO S, WANG H, YIN Y. Microglia polarization from M1 to M2 in neurodegenerative diseases[J]. Front Aging Neurosci, 2022, 14: 815347.

[7] RAVENHILL S M, EVANS A H, CREWTHER S G. Escalating bi-directional feedback loops between proinflammatory microglia and mitochondria in ageing and post-diagnosis of Parkinson's disease[J]. Antioxidants, 2023, 12(5): 1117.

[8] KAUR D, SHARMA V, DESHMUKH R. Activation of microglia and astrocytes: A roadway to neuroinflammation and Alzheimer's disease[J]. Inflammopharmacology, 2019, 27(4): 663-677.

[9] SHUI X, CHEN J, FU Z, et al. Microglia in ischemic stroke: Pathogenesis insights and therapeutic challenges[J]. J Inflamm Res, 2024, 17(2024): 3335-3352.

[10] SURINKAEW P, SAWADDIRUK P, APAIJAI N, et al. Role of microglia under cardiac and cerebral ischemia/reperfusion (I/R) injury[J]. Metab Brain Dis, 2018, 33(4): 1019-1030.

[11] WEE YONG V. Microglia in multiple sclerosis: Protectors turn destroyers[J]. Neuron, 2022, 110(21): 3534-3548.

[12] LIU J, CHENG Y, ZHENG M, et al. Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways[J]. Signal Transduct Target Ther, 2021, 6(1): 28.

[13] DIKIC I, SCHULMAN B A. An expanded lexicon for the ubiquitin code[J]. Nat Rev Mol Cell Biol, 2023, 24(4): 273-287.

[14] MA Q, RUAN H, PENG L, et al. Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity[J]. Proc Natl Acad Sci U S A, 2017, 114(41): E8760-E8769.

[15] OHTAKE F, TSUCHIYA H, SAEKI Y, et al. K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains[J]. Proc Natl Acad Sci U S A, 2018, 115(7): E1401-E1408.

[16] LANGE S M, ARMSTRONG L A, KULATHU Y. Deubiquitinases: From mechanisms to their inhibition by small molecules[J]. Mol Cell, 2022, 82(1): 15-29.

[17] JIANG Q, ZHU Z, MAO X. Ubiquitination is a major modulator for the activation of inflammasomes and pyroptosis[J]. Biochim Biophys Acta Gene Regul Mech, 2023, 1866(3): 194955.

[18] XU X, GAO F, CHEN Q, et al. F-box/LRR-repeat protein 12 reorchestrated microglia to inhibit scarring and achieve adult spinal cord injury repair[J]. Signal Transduct Target Ther, 2025, 10(1): 259.

[19] SUN J, CHEN F, SHE L, et al. YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer's disease[J]. Acta Pharm Sin B, 2025, 15(1): 331-348.

[20] TANG C, WANG M, WANG P, et al. Neural stem cells behave as a functional niche for the maturation of newborn neurons through the secretion of PTN[J]. Neuron, 2019, 101(1): 32-44. e6.

[21] NIKOLAKOPOULOU A M, MONTAGNE A, KISLER K, et al. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss[J]. Nat Neurosci, 2019, 22(7): 1089-1098.

[22] WU C, XU G, BAO G, et al. Ubiquitin ligase Triad1 promotes neurite outgrowth by inhibiting MDM2-mediated ubiquitination of the neuroprotective factor pleiotrophin[J]. J Biol Chem, 2022, 298(10): 102443.

[23] LONG Y, LI X Q, DENG J, et al. Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases[J]. Ageing Res Rev, 2024, 93: 102160.

[24] YU J, FENG D, BAO L, et al. TRIM32 inhibits NEK7 ubiquitylation-dependent microglia pyroptosis after spinal cord injury[J]. Mol Biotechnol, 2025, 67(1): 138-148.

[25] JING G, GONG H, WANG H, et al. OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis[J]. J Neuroinflammation, 2025, 22(1): 154.

[26] WU M, TU H Q, CHANG Y, et al. USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability[J]. Oncotarget, 2017, 8(2): 2197-2208.

[27] TAO W, ZHANG G, LIU C, et al. Low-dose LPS alleviates early brain injury after SAH by modulating microglial M1/M2 polarization via USP19/FOXO1/IL-10/IL-10R1 signaling[J]. Redox Biol, 2023, 66: 102863.

[28] ZHAO Y, LI T, ZHANG L, et al. TRAF6 promotes spinal microglial M1 polarization to aggravate neuropathic pain by activating the c-JUN/NF-kB signaling pathway[J]. Cell Biol Toxicol, 2024, 40(1): 54.

[29] HAN C, YAN P, HE T, et al. PHLDA1 promotes microglia-mediated neuroinflammation via regulating K63-linked ubiquitination of TRAF6[J]. Brain Behav Immun, 2020, 88: 640-653.

[30] SU P, YAN S, CHEN K, et al. EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice[J]. Mol Psychiatry, 2024, 29(4): 1099-1113.

[31] XU J, YU T, PIETRONIGRO E C, et al. Peli1 impairs microglial Aβ phagocytosis through promoting C/EBPβ degradation[J]. PLoS Biol, 2020, 18(10): e3000837.

[32] ZHANG L, TANG Y, HUANG P, et al. Role of NLRP3 inflammasome in central nervous system diseases[J]. Cell Biosci, 2024, 14(1): 75.

[33] ZHANG D, ZHANG Y, PAN J, et al. Degradation of NLRP3 by p62-dependent-autophagy improves cognitive function in Alzheimer's disease by maintaining the phagocytic function of microglia[J]. CNS Neurosci Ther, 2023, 29(10): 2826-2842.

[34] LIU Y Y, DU T S, LIU Y, et al. [Phagocytosis of microglia in neurodegenerative diseases][J]. Sheng Li Xue Bao, 2022, 74(2): 283-293.

[35] YADAV D, LEE J Y, CHAUHAN P S, et al. Modulating the ubiquitin-proteasome system: A therapeutic strategy for autoimmune diseases[J]. Cells, 2022, 11(7): 1093.

[36] LEHMAN N L. The ubiquitin proteasome system in neuropathology[J]. Acta Neuropathol, 2009, 118(3): 329-347.

[37] HUANG J, ZHU Z, SCHLÜTER D, et al. Ubiquitous regulation of cerebrovascular diseases by ubiquitin-modifying enzymes[J]. Clin Transl Med, 2024, 14(5): e1719.

[38] KAM T I, HINKLE J T, DAWSON T M, et al. Microglia and astrocyte dysfunction in Parkinson's disease[J]. Neurobiol Dis, 2020, 144: 105028.

[39] LEE E, HWANG I, PARK S, et al. MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration[J]. Cell Death Differ, 2019, 26(2): 213-228.

[40] YU H, CHANG Q, SUN T, et al. Metabolic reprogramming and polarization of microglia in Parkinson's disease: Role of inflammasome and iron[J]. Ageing Res Rev, 2023, 90: 102032.

[41] DIONÍSIO P E A, OLIVEIRA S R, AMARAL J, et al. Loss of microglial Parkin inhibits necroptosis and contributes to neuroinflammation[J]. Mol Neurobiol, 2019, 56(4): 2990-3004.

[42] TORRES-ODIO S, KEY J, HOEPKEN H H, et al. Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation[J]. J Neuroinflammation, 2017, 14(1): 154.

[43] PENG W, SCHRÖDER L F, SONG P, et al. Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease[J]. Sci Adv, 2023, 9(29): eadh3347.

[44] CHEN J, MAO K, YU H, et al. p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease[J]. J Neuroinflammation, 2021, 18(1): 295.

[45] HAN X, SUN S, SUN Y, et al. Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: Implications for Parkinson disease[J]. Autophagy, 2019, 15(11): 1860-1881.

[46] ZHANG F, XU J, YUAN Q, et al. Deletion of ZNRF2 exacerbates MPTP-induced Parkinson's disease by activating mTOR-mediated neuroinflammatory pathways[J]. Mol Neurobiol, 2025, 62(10): 12394-12412.

[47] DENG S, ZHANG Z, LIU L, et al. The E3 ligase c-Cbl modulates microglial phenotypes and contributes to Parkinson's disease pathology[J]. Cell Death Discov, 2025, 11(1): 184.

[48] TCW J, QIAN L, PIPALIA N H, et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia[J]. Cell, 2022, 185(13): 2213-2233. e25.

[49] CHAUSSE B, KAKIMOTO P A, KANN O. Microglia and lipids: How metabolism controls brain innate immunity[J]. Semin Cell Dev Biol, 2021, 112: 137-144.

[50] HAN C, WANG H, ZHANG M, et al. Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson's disease[J]. J Neuroinflammation, 2025, 22(1): 190.

[51] EBRAHIMI R, BORDBAR S, AZAD G, et al. Beyond neuroinflammation: Microglia at the crossroads of amyloid, tau, and neurodegeneration in Alzheimer's disease[J]. Neurol Sci, 2025, 46(11): 5591-5605.

[52] SUN Z, ZHANG X, SO K F, et al. Targeting microglia in Alzheimer's Disease: Pathogenesis and potential therapeutic strategies[J]. Biomolecules, 2024, 14(7): 833.

[53] WANG Z H, GONG K, LIU X, et al. Author correction: C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease[J]. Nat Commun, 2019, 10(1): 5452.

[54] NDOJA A, REJA R, LEE S H, et al. Ubiquitin ligase COP1 suppresses neuroinflammation by degrading c/EBPβ in microglia[J]. Cell, 2020, 182(5): 1156-1169. e12.

[55] SHE L Y, LI L Y, TANG H, et al. OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ[J]. Acta Pharmacol Sin, 2025, 46(10): 2608-2621.

[56] SHI J, SONG C, ZHANG P, et al. Microglial circDlg1 modulates neuroinflammation by blocking PDE4B ubiquitination-dependent degradation associated with Alzheimer's disease[J]. Theranostics, 2025, 15(8): 3401-3423.

[57] ZHENG Q, LI G, WANG S, et al. Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25[J]. Sci Adv, 2021, 7(1): eabe1340.

[58] ZHENG Q, SONG B, LI G, et al. USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation[J]. J Clin Invest, 2022, 132(5): e152170.

[59] ZHANG Q, JIA M, WANG Y, et al. Cell death mechanisms in cerebral ischemia-reperfusion injury[J]. Neurochem Res, 2022, 47(12): 3525-3542.

[60] GAO X, SU G, CHAI M, et al. Research progress on mechanisms of ischemic stroke: Regulatory pathways involving Microglia[J]. Neurochem Int, 2024, 172: 105656.

[61] XIA Q, ZHAN G, MAO M, et al. TRIM45 causes neuronal damage by aggravating microglia-mediated neuroinflammation upon cerebral ischemia and reperfusion injury[J]. Exp Mol Med, 2022, 54(2): 180-193.

[62] LI Z, LIU B, LAMBERTSEN K L, et al. USP25 inhibits neuroinflammatory responses after cerebral ischemic stroke by deubiquitinating TAB2[J]. Adv Sci, 2023, 10(28): e2301641.

[63] ZHENG S, LI Y, SONG X, et al. OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2[J]. J Neuroinflammation, 2023, 20(1): 281.

[64] LIN S X, SHI C, ZHAO L, et al. The ubiquitination and degradation of SH2B3 mediated by MEF2A/WWP2 axis restores microglial homeostasis to alleviate cerebral microvascular endothelial cell injury in ischemic stroke[J]. Neurochem Res, 2025, 50(3): 170.

[65] PSENICKA M W, SMITH B C, TINKEY R A, et al. Connecting neuroinflammation and neurodegeneration in multiple sclerosis: Are oligodendrocyte precursor cells a nexus of disease?[J]. Front Cell Neurosci, 2021, 15: 654284.

[66] XIAO Y, JIN J, CHANG M, et al. Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation[J]. Nat Med, 2013, 19(5): 595-602.

[67] TORRE S, POLYAK M J, LANGLAIS D, et al. USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation[J]. Nat Immunol, 2017, 18(1): 54-63.

[68] SHI Z, SUN H, TIAN X, et al. Extracellular vesicles containing miR-181a-5p as a novel therapy for experimental autoimmune encephalomyelitis-induced demyelination[J]. Int Immunopharmacol, 2024, 135: 112326.

[69] COSSU D, YOKOYAMA K, SECHI L A, et al. Potential of PINK1 and PARKIN proteins as biomarkers for active multiple sclerosis: A Japanese cohort study[J]. Front Immunol, 2021, 12: 681386.

[70] COSSU D, YOKOYAMA K, SATO S, et al. PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE)[J]. J Neuroimmunol, 2021, 359: 577694.

[71] COSSU D, YOKOYAMA K, SATO S, et al. Age related immune modulation of experimental autoimmune encephalomyelitis in PINK1 knockout mice[J]. Front Immunol, 2022, 13: 1036680.

[72] ALRUMAIHI F, ALMATROODI S A, ALHARBI H O A, et al. Pharmacological potential of kaempferol, a flavonoid in the management of pathogenesis via modulation of inflammation and other biological activities[J]. Molecules, 2024, 29(9): 2007.

[73] TANG S, GENG Y, WANG Y, et al. The roles of ubiquitination and deubiquitination of NLRP3 inflammasome in inflammation-related diseases: A review[J]. Biomol Biomed, 2024, 24(4): 708-721.

[74] ZHANG X W, FENG N, LIU Y C, et al. Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy[J]. Sci Adv, 2022, 8(32): eabo0789.

[75] ITOH K, TONG K I, YAMAMOTO M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles[J]. Free Radic Biol Med, 2004, 36(10): 1208-1213.

[76] SHAO M, GAO P, CHENG W, et al. Ginsenoside Rb3 upregulates sarcoplasmic reticulum Ca(2+)-ATPase expression and improves the contractility of cardiomyocytes by inhibiting the NF-kappaB pathway[J]. Biomed Pharmacother, 2022, 154: 113661.

[77] LI H, CUI L, LIU Q, et al. Ginsenoside Rb3 alleviates CSE-induced TROP2 upregulation through p38 MAPK and NF-kappaB pathways in basal cells[J]. Am J Respir Cell Mol Biol, 2021, 64(6): 747-759.

[78] ZHANG Q X, DU Y X, CAO J J, et al. Ginsenoside Rb3 represses CPZ-induced demyelination and neuroinflammation by inhibiting TRAF6 K63 ubiquitination[J]. Int Immunopharmacol, 2025, 158: 114800.

基金资助

国家自然科学基金项目(82360254)

甘肃省自然科学基金项目(24JRRA359)

兰州市城关区科技人才创新创业项目(2023RCCX0012)