Ubiquitous regulation of cerebrovascular diseases by ubiquitin-modifying enzymes

Abstract

Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the development of efficacious preventative and therapeutic approaches. Accumulating studies have highlighted the significance of ubiquitin-modifying enzymes (UMEs) in the regulation of CVDs. UMEs are a group of enzymes that orchestrate ubiquitination, a post-translational modification tightly involved in CVDs. Functionally, UMEs regulate multiple pathological processes in ischemic and hemorrhagic stroke, moyamoya disease, and atherosclerosis. Considering the important roles of UMEs in CVDs, they may become novel druggable targets for these diseases. Besides, techniques applying UMEs, such as proteolysis-targeting chimera and deubiquitinase-targeting chimera, may also revolutionize the therapy of CVDs in the future.

Keywords

cerebrovascular disease / deubiquitinating enzyme / disease mechanism / therapeutic target / ubiquitinating enzyme / ubiquitination

References

[1] Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends Neurosci. 2013;36(10):587-597.

[2] Belanger M, Allaman I, Magistretti PJ. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011;14(6):724-738.

[3] Xing CY, Tarumi T, Liu J, et al. Distribution of cardiac output to the brain across the adult lifespan. J Cereb Blood Flow Metab. 2017;37(8):2848-2856.

[4] Claassen J, Thijssen DHJ, Panerai RB, Faraci FM. Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation. Physiol Rev. 2021;101(4):1487-1559.

[5] Gutierrez J, Khasiyev F, Liu M, et al. Determinants and outcomes of asymptomatic intracranial atherosclerotic stenosis. J Am Coll Cardiol. 2021;78(6):562-571.

[6] Banerjee C, Chimowitz MI. Stroke caused by atherosclerosis of the major intracranial arteries. Circ Res. 2017;120(3):502-513.

[7] Ihara M, Yamamoto Y, Hattori Y, et al. Moyamoya disease: diagnosis and interventions. Lancet Neurol. 2022;21(8):747-758.

[8] Asselman C, Hemelsoet D, Eggermont D, Dermaut B, Impens F. Moyamoya disease emerging as an immune-related angiopathy. Trends Mol Med. 2022;28(11):939-950.

[9] Tekle WG, Hassan AE. Intracranial Atherosclerotic disease: current concepts in medical and surgical management. Neurology. 2021;97(20):S145-S157. Suppl 2

[10] Owolabi MO, Thrift AG, Mahal A, et al. Primary stroke prevention worldwide: translating evidence into action. Lancet Public Health. 2022;7(1):e74-e85.

[11] Liu H, Sun S, Liu B. Smurf2 exerts neuroprotective effects on cerebral ischemic injury. J Biol Chem. 2021;297(2):100537.

[12] Yu YL, Chou RH, Shyu WC, et al. Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke. EMBO Mol Med. 2013;5(4):531-547.

[13] Zeng J, Wang Y, Luo Z, et al. TRIM9-Mediated resolution of neuroinflammation confers neuroprotection upon ischemic stroke in mice. Cell Rep. 2019;27(2):549-560. e6

[14] Liu H, Povysheva N, Rose ME, et al. Role of UCHL1 in axonal injury and functional recovery after cerebral ischemia. Proc Natl Acad Sci U S A. 2019;116(10):4643-4650.

[15] Roy V, Ross JP, Pepin R, et al. Moyamoya disease susceptibility gene RNF213 regulates endothelial barrier function. Stroke. 2022;53(4):1263-1275.

[16] Ndoja A, Reja R, Lee SH, et al. Ubiquitin ligase COP1 suppresses neuroinflammation by degrading c/EBPbeta in microglia. Cell. 2020;182(5):1156-1169. e12

[17] Heger K, Wickliffe KE, Ndoja A, et al. OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature. 2018;559(7712):120-124.

[18] Zheng N, Shabek N. Ubiquitin ligases: Structure, function, and regulation. Annu Rev Biochem. 2017;86:129-157.

[19] Berndsen CE, Wolberger C. New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol. 2014;21(4):301-307.

[20] Harrigan JA, Jacq X, Martin NM, Jackson SP. Deubiquitylating enzymes and drug discovery: Emerging opportunities. Nat Rev Drug Discovery. 2018;17(1):57-78.

[21] Deol KK, Lorenz S, Strieter ER. Enzymatic logic of ubiquitin chain assembly. Front Physiol. 2019;10:835.

[22] Clague MJ, Urbe S, Komander D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol. 2019;20(6):338-352.

[23] Liu B, Ruan J, Chen M, et al. Deubiquitinating enzymes (DUBs): Decipher underlying basis of neurodegenerative diseases. Mol Psychiatry. 2022;27(1):259-268.

[24] Juang YC, Landry MC, Sanches M, et al. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function. Mol Cell. 2012;45(3):384-397.

[25] Wiener R, Zhang X, Wang T, Wolberger C. The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature. 2012;483(7391):618-622.

[26] Nakada S, Tai I, Panier S, et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010;466(7309):941-946.

[27] Sheng X, Xia Z, Yang H, Hu R. The ubiquitin codes in cellular stress responses. Protein Cell. 2023;15(3):157-190.

[28] Gu W, Zhang J, Li Q, et al. The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation. Cell Discovery. 2023;9(1):82.

[29] Brigant B, Demont Y, Ouled-Haddou H, et al. TRIM37 is highly expressed during mitosis in CHON-002 chondrocytes cell line and is regulated by miR-223. Bone. 2020;137:115393.

[30] Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542.

[31] Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet. 2011;56(1):34-40.

[32] Liu W, Hitomi T, Kobayashi H, Harada KH, Koizumi A. Distribution of moyamoya disease susceptibility polymorphism p.R4810K in RNF213 in East and Southeast Asian populations. Neurol Med Chir. 2012;52(5):299-303.

[33] Jang MA, Shin S, Yoon JH, Ki CS. Frequency of the moyamoya-related RNF213 p.Arg4810Lys variant in 1,516 Korean individuals. BMC Med Genet. 2015;16:109.

[34] Xue Y, Zeng C, Ge P, et al. Association of RNF213 variants with periventricular anastomosis in moyamoya disease. Stroke. 2022;53(9):2906-2916.

[35] Collaborators GBDS. Global, regional, and national burden of stroke, 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019;18(5):439-458.

[36] Hankey GJ. Stroke. Lancet. 2017;389(10069):641-654.

[37] Prabhakaran S, Ruff I, Bernstein RA. Acute stroke intervention: a systematic review. JAMA. 2015;313(14):1451-1462.

[38] Bavarsad K, Barreto GE, Hadjzadeh MA, Sahebkar A. Protective effects of curcumin against ischemia-reperfusion injury in the nervous system. Mol Neurobiol. 2019;56(2):1391-1404.

[39] Naito MG, Xu D, Amin P, et al. Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke. Proc Natl Acad Sci U S A. 2020;117(9):4959-4970.

[40] Green DR. The coming decade of cell death research: five riddles. Cell. 2019;177(5):1094-1107.

[41] Galluzzi L, Kepp O, Chan FK, Kroemer G. Necroptosis: mechanisms and relevance to disease. Annu Rev Pathol. 2017;12:103-130.

[42] Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20(1):19-33.

[43] Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517(7534):311-320.

[44] Deng XX, Li SS, Sun FY. Necrostatin-1 Prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-mediated RIPK3/MLKL signaling. Aging Dis. 2019;10(4):807-817.

[45] Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112-119.

[46] Li J, Zhang J, Zhang Y, et al. TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis. Cell Death Dis. 2019;10(5):328.

[47] Yao D, Zhang S, Hu Z, et al. CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation. Aging (Albany NY). 2021;13(23):25564-25577.

[48] Yuan Z, Yi-Yun S, Hai-Yan Y. Triad3A displays a critical role in suppression of cerebral ischemic/reperfusion (I/R) injury by regulating necroptosis. Biomed Pharmacother. 2020;128:110045.

[49] Cabral-Miranda F, Nicoloso-Simoes E, Adao-Novaes J, et al. rAAV8-733-Mediated gene transfer of CHIP/Stub-1 prevents hippocampal neuronal death in experimental brain ischemia. Mol Ther. 2017;25(2):392-400.

[50] Rodriguez C, Ramos-Araque ME, Dominguez-Martinez M, et al. Single-nucleotide polymorphism 309T>G in the MDM2 promoter determines functional outcome after stroke. Stroke. 2018;49(10):2437-2444.

[51] Zhu X, Li J, You D, Xiao Y, Huang Z, Yu W. Neuroprotective effect of E3 ubiquitin ligase RNF8 against ischemic stroke via HDAC2 stability reduction and reelin-dependent GSK3beta inhibition. Mol Neurobiol. 2022;59(8):4776-4790.

[52] Gu C, Yang J, Luo Y, et al. ZNRF2 attenuates focal cerebral ischemia/reperfusion injury in rats by inhibiting mTORC1-mediated autophagy. Exp Neurol. 2021;342:113759.

[53] Wang L, Lu Y, Guan H, et al. Tumor necrosis factor receptor-associated factor 5 is an essential mediator of ischemic brain infarction. J Neurochem. 2013;126(3):400-414.

[54] Li T, Qin JJ, Yang X, et al. The Ubiquitin E3 Ligase TRAF6 exacerbates ischemic stroke by ubiquitinating and activating Rac1. J Neurosci. 2017;37(50):12123-12140.

[55] Gong J, Li ZZ, Guo S, et al. Neuron-Specific tumor necrosis factor receptor-associated factor 3 is a central regulator of neuronal death in acute ischemic stroke. Hypertension. 2015;66(3):604-616.

[56] Gomez-Sanchez JC, Delgado-Esteban M, Rodriguez-Hernandez I, et al. The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke. J Exp Med. 2011;208(3):429-437.

[57] Rodriguez C, Sobrino T, Agulla J, et al. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism. Cell Death Differ. 2017;24(1):144-154.

[58] Ouyang S, Song Y, Tian Y, Chen Y, Yu X, Wang D. RNF8 deficiency results in neurodegeneration in mice. Neurobiol Aging. 2015;36(10):2850-2860.

[59] Mailand N, Bekker-Jensen S, Faustrup H, et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell. 2007;131(5):887-900.

[60] Wang Y, Liu G, Hong D, Chen F, Ji X, Cao G. White matter injury in ischemic stroke. Prog Neurobiol. 2016;141:45-60.

[61] Stetler RA, Gao Y, Leak RK, et al. APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proc Natl Acad Sci U S A. 2016;113(25):E3558-E3567.

[62] Liu H, Li W, Rose ME, et al. The point mutation UCH-L1 C152A protects primary neurons against cyclopentenone prostaglandin-induced cytotoxicity: implications for post-ischemic neuronal injury. Cell Death Dis. 2015;6(11):e1966.

[63] Shichita T, Ooboshi H, Yoshimura A. Neuroimmune mechanisms and therapies mediating post-ischaemic brain injury and repair. Nat Rev Neurosci. 2023;24(5):299-312.

[64] Heckmann BL, Tummers B, Green DR. Crashing the computer: apoptosis vs. necroptosis in neuroinflammation. Cell Death Differ. 2019;26(1):41-52.

[65] Xiao Y, Jin J, Chang M, et al. Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation. Nat Med. 2013;19(5):595-602.

[66] Wang X, Deckert M, Xuan NT, et al. Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-kappaB- and STAT1-dependent chemokine production in astrocytes. Acta Neuropathol. 2013;126(5):711-724.

[67] Mulas F, Wang X, Song S, et al. The deubiquitinase OTUB1 augments NF-kappaB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13. Cell Mol Immunol. 2021;18(6):1512-1527.

[68] Wang X, Mulas F, Yi W, et al. OTUB1 inhibits CNS autoimmunity by preventing IFN-gamma-induced hyperactivation of astrocytes. EMBO J. 2019;38(10):e100947.

[69] Cruz JA, Mokashi CS, Kowalczyk GJ, et al. A variable-gain stochastic pooling motif mediates information transfer from receptor assemblies into NF-kappaB. Sci Adv. 2021;7(30):eabi9410.

[70] Tarantino N, Tinevez JY, Crowell EF, et al. TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO-IKK supramolecular structures. J Cell Biol. 2014;204(2):231-245.

[71] Bai X, Zhang YL, Liu LN. Inhibition of TRIM8 restrains ischaemia-reperfusion-mediated cerebral injury by regulation of NF-kappaB activation associated inflammation and apoptosis. Exp Cell Res. 2020;388(2):111818.

[72] Xia Q, Zhan G, Mao M, Zhao Y, Li X. TRIM45 causes neuronal damage by aggravating microglia-mediated neuroinflammation upon cerebral ischemia and reperfusion injury. Exp Mol Med. 2022;54(2):180-193.

[73] Hao MQ, Xie LJ, Leng W, Xue RW. Trim47 is a critical regulator of cerebral ischemia-reperfusion injury through regulating apoptosis and inflammation. Biochem Biophys Res Commun. 2019;515(4):651-657.

[74] Liu X, Lei Q. TRIM62 knockout protects against cerebral ischemic injury in mice by suppressing NLRP3-regulated neuroinflammation. Biochem Biophys Res Commun. 2020;529(2):140-147.

[75] Wang L, Wu D, Xu Z. USP10 protects against cerebral ischemia injury by suppressing inflammation and apoptosis through the inhibition of TAK1 signaling. Biochem Biophys Res Commun. 2019;516(4):1272-1278.

[76] Xiang J, Zhang X, Fu J, Wang H, Zhao Y. USP18 overexpression protects against focal cerebral ischemia injury in mice by suppressing microglial activation. Neuroscience. 2019;419:121-128.

[77] Pan R, Xie Y, Fang W, Liu Y, Zhang Y. USP20 mitigates ischemic stroke in mice by suppressing neuroinflammation and neuron death via regulating PTEN signal. Int Immunopharmacol. 2022;103:107840.

[78] Li Z, Liu B, Lambertsen KL, et al. USP25 inhibits neuroinflammatory responses after cerebral ischemic stroke by deubiquitinating TAB2. Adv Sci. 2023;10(28):e2301641.

[79] Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer. 2008;8(6):438-449.

[80] Shi M, Cho H, Inn KS, et al. Negative regulation of NF-kappaB activity by brain-specific TRIpartite Motif protein 9. Nat Commun. 2014;5:4820.

[81] Spitzer D, Guerit S, Puetz T, et al. Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke. Acta Neuropathol. 2022;144(2):305-337.

[82] Yu H, Luo H, Chang L, et al. The NEDD8-activating enzyme inhibitor MLN4924 reduces ischemic brain injury in mice. Proc Natl Acad Sci U S A. 2022;119(6):e2111896119.

[83] Narne P, Pandey V, Phanithi PB. Interplay between mitochondrial metabolism and oxidative stress in ischemic stroke: an epigenetic connection. Mol Cell Neurosci. 2017;82:176-194.

[84] Ren KD, Liu WN, Tian J, et al. Mitochondrial E3 ubiquitin ligase 1 promotes brain injury by disturbing mitochondrial dynamics in a rat model of ischemic stroke. Eur J Pharmacol. 2019;861:172617.

[85] Prudent J, Zunino R, Sugiura A, Mattie S, Shore GC, McBride HM. MAPL SUMOylation of Drp1 stabilizes an ER/mitochondrial platform required for cell death. Mol Cell. 2015;59(6):941-955.

[86] Sisalli MJ, Ianniello G, Savoia C, Cuomo O, Annunziato L, Scorziello A. Knocking-out the Siah2 E3 ubiquitin ligase prevents mitochondrial NCX3 degradation, regulates mitochondrial fission and fusion, and restores mitochondrial function in hypoxic neurons. Cell Commun Signal. 2020;18(1):42.

[87] Carlucci A, Adornetto A, Scorziello A, et al. Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia. EMBO J. 2008;27(7):1073-1084.

[88] Zhang X, Yan H, Yuan Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013;9(9):1321-1333.

[89] Geisler S, Holmstrom KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119-131.

[90] Zhang X, Yuan Y, Jiang L, et al. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy. Autophagy. 2014;10(10):1801-1813.

[91] Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: A systematic review. Lancet Neurol. 2009;8(4):355-369.

[92] Claassen J, Park S. Spontaneous subarachnoid haemorrhage. Lancet. 2022;400(10355):846-862.

[93] Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42(6):1781-1786.

[94] Meng Z, Zhao T, Zhou K, et al. A20 Ameliorates intracerebral hemorrhage-induced inflammatory injury by regulating TRAF6 polyubiquitination. J Immunol. 2017;198(2):820-831.

[95] Qu X, Wang N, Chen W, Qi M, Xue Y, Cheng W. RNF34 overexpression exacerbates neurological deficits and brain injury in a mouse model of intracerebral hemorrhage by potentiating mitochondrial dysfunction-mediated oxidative stress. Sci Rep. 2019;9(1):16296.

[96] Zhang S, Hu ZW, Luo HY, et al. AAV/BBB-mediated gene transfer of CHIP attenuates brain injury following experimental intracerebral hemorrhage. Transl Stroke Res. 2020;11(2):296-309.

[97] Liu C, Liu C, Liu H, et al. Increased expression of ubiquitin-specific protease 4 participates in neuronal apoptosis after intracerebral hemorrhage in adult rats. Cell Mol Neurobiol. 2017;37(3):427-435.

[98] Xu Z, Li X, Chen J, et al. USP11, Deubiquitinating enzyme, associated with neuronal apoptosis following intracerebral hemorrhage. J Mol Neurosci. 2016;58(1):16-27.

[99] Ma A, Malynn BA. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol. 2012;12(11):774-785.

[100] Ruan J, Schluter D, Naumann M, Waisman A, Wang X. Ubiquitin-modifying enzymes as regulators of colitis. Trends Mol Med. 2022;28(4):304-318.

[101] Razani B, Whang MI, Kim FS, et al. Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation. Nat Immunol. 2020;21(4):422-433.

[102] St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127(2):397-408.

[103] Chu X, Wu X, Feng H, et al. Coupling between interleukin-1R1 and necrosome complex involves in hemin-induced neuronal necroptosis after intracranial hemorrhage. Stroke. 2018;49(10):2473-2482.

[104] Shen H, Liu C, Zhang D, et al. Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro. Cell Death Dis. 2017;8(3):e2641.

[105] Seo J, Lee EW, Sung H, et al. CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3. Nat Cell Biol. 2016;18(3):291-302.

[106] Chen S, Feng H, Sherchan P, et al. Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog Neurobiol. 2014;115:64-91.

[107] Mabb AM, Je HS, Wall MJ, et al. Triad3A regulates synaptic strength by ubiquitination of arc. Neuron. 2014;82(6):1299-1316.

[108] Chen T, Zhu J, Wang YH. RNF216 mediates neuronal injury following experimental subarachnoid hemorrhage through the Arc/Arg3.1-AMPAR pathway. FASEB J. 2020;34(11):15080-15092.

[109] Zhou Y, Tao T, Liu G, et al. TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-kappaB pathways. Cell Death Dis. 2021;12(1):10.

[110] Huang XP, Peng JH, Pang JW, et al. Peli1 Contributions in microglial activation, neuroinflammatory responses and neurological deficits following experimental subarachnoid hemorrhage. Front Mol Neurosci. 2017;10:398.

[111] Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009;360(12):1226-1237.

[112] Kuroda S, Houkin K. Moyamoya disease: Current concepts and future perspectives. Lancet Neurol. 2008;7(11):1056-1066.

[113] Ahel J, Lehner A, Vogel A, et al. Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism. eLife. 2020;9:e56185.

[114] Bhardwaj A, Banh RS, Zhang W, Sidhu SS, Neel BG. MMD-associated RNF213 SNPs encode dominant-negative alleles that globally impair ubiquitylation. Life Sci Alliance. 2022;5(5):e202000807.

[115] Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. 2019;124(2):315-327.

[116] Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2022 update: A report from the American Heart Association. Circulation. 2022;145(8):e153-e639.

[117] Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet. 2014;383(9921):984-998.

[118] Bang OY, Chung JW, Cha J, et al. A polymorphism in RNF213 is a susceptibility gene for intracranial atherosclerosis. PLoS One. 2016;11(6):e0156607.

[119] Okazaki S, Morimoto T, Kamatani Y, et al. Moyamoya disease susceptibility variant RNF213 p.R4810K Increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation. 2019;139(2):295-298.

[120] Kamimura T, Okazaki S, Morimoto T, et al. Prevalence of RNF213 p.R4810K variant in early-onset stroke with intracranial arterial stenosis. Stroke. 2019;50(6):1561-1563.

[121] Miyawaki S, Imai H, Shimizu M, et al. Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion. Stroke. 2013;44(10):2894-2897.

[122] Kim HJ, Choi EH, Chung JW, et al. Role of the RNF213 variant in vascular outcomes in patients with intracranial atherosclerosis. J Am Heart Assoc. 2021;10(1):e017660.

[123] Wang X, Wang Y, Antony V, Sun H, Liang G. Metabolism-associated molecular patterns (MAMPs). Trends Endocrinol Metab. 2020;31(10):712-724.

[124] Kunjathoor VV, Febbraio M, Podrez EA, et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002;277(51):49982-49988.

[125] Chinetti-Gbaguidi G, Colin S, Staels B. Macrophage subsets in atherosclerosis. Nat Rev Cardiol. 2015;12(1):10-17.

[126] Shankman LS, Gomez D, Cherepanova OA, et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med. 2015;21(6):628-637.

[127] Skalen K, Gustafsson M, Rydberg EK, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002;417(6890):750-754.

[128] Li Q, Xuan W, Jia Z, et al. HRD1 prevents atherosclerosis-mediated endothelial cell apoptosis by promoting LOX-1 degradation. Cell Cycle. 2020;19(12):1466-1477.

[129] Zeng Y, Cao J, Li CX, Wang CY, Wu RM, Xu XL. MDM2-mediated ubiquitination of RXRbeta contributes to mitochondrial damage and related inflammation in atherosclerosis. Int J Mol Sci. 2022;23(10):5766.

[130] Wang X, Ma L, Zhang S, Song Q, He X, Wang J. WWP2 ameliorates oxidative stress and inflammation in atherosclerotic mice through regulation of PDCD4/HO-1 pathway. Acta Biochim Biophys Sin. 2022;54(8):1057-1067.

[131] Akhmedov A, Sawamura T, Chen CH, Kraler S, Vdovenko D, Luscher TF. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease. Eur Heart J. 2021;42(18):1797-1807.

[132] Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, Silverstein RL. A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 2006;4(3):211-221.

[133] Wang B, Tang X, Yao L, et al. Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis. J Clin Invest. 2022;132(10):e154217.

[134] Tran TT, Poirier H, Clement L, et al. Luminal lipid regulates CD36 levels and downstream signaling to stimulate chylomicron synthesis. J Biol Chem. 2011;286(28):25201-25210.

[135] Srikanthan S, Li W, Silverstein RL, McIntyre TM. Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. J Thromb Haemost. 2014;12(11):1906-1917.

[136] Xia X, Hu T, He J, et al. USP10 deletion inhibits macrophage-derived foam cell formation and cellular-oxidized low density lipoprotein uptake by promoting the degradation of CD36. Aging. 2020;12(22):22892-22905.

[137] Zhang F, Xia X, Chai R, et al. Inhibition of USP14 suppresses the formation of foam cell by promoting CD36 degradation. J Cell Mol Med. 2020;24(6):3292-3302.

[138] Xia X, Xu Q, Liu M, et al. Deubiquitination of CD36 by UCHL1 promotes foam cell formation. Cell Death Dis. 2020;11(8):636.

[139] Ji R, Gu Y, Zhang J, et al. TRIM7 promotes proliferation and migration of vascular smooth muscle cells in atherosclerosis through activating c-Jun/AP-1. IUBMB Life. 2020;72(2):247-258.

[140] Burger F, Baptista D, Roth A, Brandt KJ, Miteva K. The E3 ubiquitin ligase peli1 deficiency promotes atherosclerosis progression. Cells. 2022;11(13):11132014.

[141] Soehnlein O, Libby P. Targeting inflammation in atherosclerosis—from experimental insights to the clinic. Nat Rev Drug Discovery. 2021;20(8):589-610.

[142] Roy P, Orecchioni M, Ley K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol. 2022;22(4):251-265.

[143] Wolfrum S, Teupser D, Tan M, Chen KY, Breslow JL. The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappaB target genes. Proc Natl Acad Sci U S A. 2007;104(47):18601-18606.

[144] Zhu C, Chen W, Cui H, et al. TRIM64 promotes ox-LDL-induced foam cell formation, pyroptosis, and inflammation in THP-1-derived macrophages by activating a feedback loop with NF-kappaB via IkappaBalpha ubiquitination. Cell Biol Toxicol. 2023;39(3):607-620.

[145] Wang C, Xu W, Chao Y, Liang M, Zhang F, Huang K. E3 ligase FBXW2 is a new therapeutic target in obesity and atherosclerosis. Adv Sci. 2020;7(20):2001800.

[146] Chandra D, Londino J, Alexander S, et al. The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis. J Mol Cell Cardiol. 2019;126:50-59.

[147] Liu M, Yan M, Lv H, et al. Macrophage K63-linked ubiquitination of YAP promotes its nuclear localization and exacerbates atherosclerosis. Cell Rep.2020;32(5):107990.

[148] Wertz IE, O'Rourke KM, Zhou H, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004;430(7000):694-699.

[149] Martens A, Priem D, Hoste E, et al. Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities. Nat Immunol. 2020;21(4):381-387.

[150] Kyaw T, Winship A, Tay C, et al. Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoE-deficient mice. Circulation. 2013;127(9):1028-1039.

[151] Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387-401.

[152] Seijkens TTP, Poels K, Meiler S, et al. Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death. Eur Heart J. 2019;40(4):372-382.

[153] Jean-Charles PY, Wu JH, Zhang L, et al. USP20 (ubiquitin-specific protease 20) inhibits TNF (tumor necrosis factor)-triggered smooth muscle cell inflammation and attenuates atherosclerosis. Arterioscler, Thromb, Vasc Biol. 2018;38(10):2295-2305.

[154] Min JW, Lu L, Freeling JL, Martin DS, Wang H. USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice. J Neurochem. 2017;140(5):826-833.

[155] Hou W, Yao J, Liu J, et al. USP14 inhibition promotes recovery by protecting BBB integrity and attenuating neuroinflammation in MCAO mice. CNS Neurosci Ther. 2023;29(11):3612-3623.

[156] Lange SM, Armstrong LA, Kulathu Y. Deubiquitinases: from mechanisms to their inhibition by small molecules. Mol Cell. 2022;82(1):15-29.

[157] Chan WC, Liu X, Magin RS, et al. Accelerating inhibitor discovery for deubiquitinating enzymes. Nat Commun. 2023;14(1):686.

[158] Ren J, Yu P, Liu S, et al. Deubiquitylating Enzymes in Cancer and Immunity. Adv Sci. 2023;10(36):e2303807.

[159] Pabon NA, Zhang Q, Cruz JA, Schipper DL, Camacho CJ, Lee REC. A network-centric approach to drugging TNF-induced NF-kappaB signaling. Nat Commun. 2019;10(1):860.

[160] Farrell K, Jarome TJ. Is PROTAC technology really a game changer for central nervous system drug discovery?Expert Opin Drug Discovery. 2021;16(8):833-840.

[161] Bekes M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discovery. 2022;21(3):181-200.

[162] Henning NJ, Boike L, Spradlin JN, et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat Chem Biol. 2022;18(4):412-421.

[163] Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 update: A report from the American Heart Association. Circulation. 2021;143(8):e254-e743.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.