李昕云,郭新建

PSMB4作为26S蛋白酶体的核心亚基之一，在维持细胞内蛋白质稳态中发挥关键作用。近年来发现可在多种疾病中发挥着重要的作用，尤其是在肿瘤发生发展、病毒感染及免疫相关疾病中扮演重要角色。本文将从PSMB4的分子结构与功能出发，系统综述其在肿瘤、病毒感染、免疫调节中的多维度作用机制及临床应用前景。重点阐述PSMB4通过蛋白酶体依赖与非依赖途径调控疾病进程的相关机制，深入探讨其表达水平与多种恶性肿瘤临床病理特征及患者预后的关联。以期为疾病的诊疗提供一定的参考及思路。

PSMB4；蛋白酶体；肿瘤发生；病毒感染；分子机制；治疗靶点

[1] Nothwang HG,Tamura T,Tanaka K,Ichihara A.Sequence analyses and inter-species comparisons of three novel human proteasomal subunits,HsN3,HsC7-I and HsC10-II,confine potential proteolytic active-site residues.Biochim Biophys Acta.1994.1219(2):361-8. [2] Murata S,Yashiroda H,Tanaka K.Molecular mechanisms of proteasome assembly.Nat Rev Mol Cell Biol.2009.10(2):104-15. [3] COUX O,TANAKA K,GOLDBERG A L.Structure and functions of the 20S and 26S proteasomes[J].Annu Rev Biochem, 1996,65:801-847. [4] Hirano Y,Kaneko T,Okamoto K,et al.Dissecting beta-ring assembly pathway of the mammalian 20S proteasome.EMBO J.2008.27(16):2204-13. [5] BAUMEISTER W,WALZ J,ZüHL F,et al.The proteasome:paradigm of a self-compartmentalizing protease[J].Cell,1998,92(3):367-380. [6] HEINEMEYER W,RAMOS P C,DOHMEN R J.The ultimate nanoscale mincer:assembly,structure and active sites of the 20S proteasome core[J].Cell Mol Life Sci,2004,61(13):1562-1578. [7] CIECHANOVER A,ORIAN A,SCHWARTZ A L.Ubiquitin-mediated proteolysis:biological regulation via destruction[J].Bioessays, 2000,22(5):442-451. [8] CHITRA S,NALINI G,RAJASEKHAR G.The ubiquitin proteasome system and efficacy of proteasome inhibitors in diseases[J].Int J Rheum Dis,2012,15(3):249-260. [9] SCHEFFNER M,HUIBREGTSE J M,VIERSTRA R D,et al.The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53[J].Cell,1993,75(3):495-505. [10] Yi H,Wang Q,Lu L,et al.PSMB4 Degrades the Porcine Reproductive and Respiratory Syndrome Virus Nsp1αProtein via the Autolysosome Pathway and Induces the Production of Type I Interferon.J Virol.2023.97(4):e0026423. [11] Wang X,Shao C,Wang L,Li Q,Song H,Fang W.The viral non-structural protein 1 alpha(Nsp1α)inhibits p53 apoptosis activity by increasing murine double minute 2(mdm2)expression in porcine reproductive and respiratory syndrome virus(PRRSV)early-infected cells.Vet Microbiol.2016.184:73-9. [12] 梁桂莲,李晓睿,徐君南,马艺文,孙涛.白桦脂酸衍生物Q-4靶向PSMB4抑制三阴性乳腺癌增殖,2025.2. [13] 张慧萍.PSMB4、NF-KBp65、BCL-2在浆液性卵巢癌中的表达及其相关性研究:延安大学,2023. [14] 刘力源.PSMB4通过NF-κB途径调控人透明细胞癌增殖的研究[D],2022. [15] 陆谦,程欣,夏振国,等.蛋白酶体β亚基4型对人肝癌SMMC7721细胞增殖存活的影响[J].临床肝胆病杂志,2020,36(03):592-595. [16] 陆谦,朱李,程欣,等.人蛋白酶体β亚基4型在肝细胞癌中的表达及与预后的关系[J].临床肝胆病杂志,2020,36(02):372-376. [17] 陆谦.PSMB4在肝细胞肝癌中的表达及其对肝癌细胞增殖和凋亡的影响研究[D],2019. [18] 夏鹏,陈金中,王臻臻,等.人蛋白酶体β亚基4型(PSMB4)与BcL-2家族中促凋亡蛋白分子Bim的相互作用[J].长江大学学报(自然科学版),2012,9(09):1-4+79. [19] THAKER N G,ZHANG F,MCDONALD P R,et al.Identification of survival genes in human glioblastoma cells by small interfering RNA screening[J].Mol Pharmacol,2009,76(6):1246-1255. [20] 夏鹏,陈金中,王瑧瑧,等.人蛋白酶体β亚基4型(PSMB4)与BcL-2家族中促凋亡蛋白分子Bim的相互作用[J].长江大学学报（自科版）医学卷,2012(9):1-4. [21] LEE K M,LEE J,PARK C S.Cereblon inhibits proteasome activity by binding to the 20S core proteasome subunit beta type 4[J].Biochem Biophys Res Commun,2012,427(3):618-622. [22] LEE G Y,HAVERTY P M,LI L,et al.Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes[J].Cancer Res,2014,74(11):3114-3126. [23] MAIRINGER F D,WALTER R F,THEEGARTEN D,et al.Gene Expression Analysis of the 26S Proteasome Subunit PSMB4 Reveals Significant Upregulation,Different Expression and Association with Proliferation in Human Pulmonary Neuroendocrine Tumours[J].J Cancer,2014,5(8):646-654. [24] QI J,ZHANG M,HE P C,et al.[Proteomic study of retinoid acid resistant NB4R1 cells apoptosis induced by realgar][J].Zhonghua Xue Ye Xue Za Zhi,2010,31(11):752-757. [25] ZAPATERO A,MORENTE M,NIETO S,et al.Predictive value of PAK6 and PSMB4 expression in patients with localized prostate cancer treated with dose-escalation radiation therapy and androgen deprivation therapy[J].Urol Oncol,2014,32(8):1327-1332. [26] ZHANG Y,LIU H,CUI M,et al.Effect of the HBV whole-X gene on the expression of hepatocellular carcinoma associated proteins[J].J Microbiol Immunol Infect,2016,49(3):335-343. [27] LIU R,LU S,DENG Y,et al.PSMB4 expression associates with epithelial ovarian cancer growth and poor prognosis[J].Arch Gynecol Obstet,2016,293(6):1297-1307. [28] ZHANG X,LIN D,LIN Y,et al.Proteasome beta-4 subunit contributes to the development of melanoma and is regulated by miR-148b[J].Tumour Biol,2017,39(6):1010428317705767. [29] MONTENEGRO-VENEGAS C,FIENKO S,ANNI D,et al.Bassoon inhibits proteasome activity via interaction with PSMB4[J].Cell Mol Life Sci,2021,78(4):1545-1563. [30] WALTER R,SYDOW S R,BERG E,et al.Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma[J].Cancer Manag Res,2019,11:8711-8720. [31] ZHOU D M,LIU J,LIU F,et al.A novel FoxM1-PSMB4 axis contributes to proliferation and progression of cervical cancer[J].Biochem Biophys Res Commun,2020,521(3):746-752. [32] WANG H,HE Z,XIA L,et al.PSMB4 overexpression enhances the cell growth and viability of breast cancer cells leading to a poor prognosis[J].Oncol Rep,2018,40(4):2343-2352. [33] LIU J,MI J,LIU S,et al.PSMB5 overexpression is correlated with tumor proliferation and poor prognosis in hepatocellular carcinoma[J].FEBS Open Bio,2022,12(11):2025-2041. [34] YANG Y,LI Y,YANG Q,et al.FAT4 activation inhibits epithelial-mesenchymal transition(EMT)by promoting autophagy in H2228/Cer cells[J].Med Oncol,2022,40(1):64. [35] PENG Z,LIANG X,LIN X,et al.Exploration of the molecular mechanisms,shared gene signatures,and MicroRNAs between systemic lupus erythematosus and diffuse large B cell lymphoma by bioinformatics analysis[J].Lupus,2022,31(11):1317-1327. [36] LIU C,LI X,GAO M,et al.Downregulation of hepatic METTL3 contributes to APAP-induced liver injury in mice[J].JHEP Rep,2023,5(8):100766. [37] LI X,LIU C,ZHANG Z,et al.Hepatocyte-specific Wtap deficiency promotes hepatocellular carcinoma by activating GRB2-ERK depending on downregulation of proteasome-related genes[J].J Biol Chem,2023,299(11):105301. [38] GARCIA J B,STORTI P,IANNOZZI N T,et al.Identification of PSMB4 and PSMD4 as novel target genes correlated with 1q21 amplification in patients with smoldering myeloma and multiple myeloma[J].Haematologica,2024,109(2):627-631. [39] LIN Y H,CHEN T M,TSAI Y L,et al.The Reduction of PSMB4 in T24 and J82 Bladder Cancer Cells Inhibits the Angiogenesis and Migration of Endothelial Cells[J].Int J Mol Sci,2024,25(10):5559. [40] BOCKORNY B,MUTHUSWAMY L,HUANG L,et al.A large-scale proteomics resource of circulating extracellular vesicles for biomarker discovery in pancreatic cancer[J].Elife,2024,12:RP87369. [41] 谭国伟,陈建彬,钱洪流,等.PSMB4亚基蛋白在脑胶质瘤中表达的相关研究[J].中华神经医学杂志,2012(10):1015-1018. [42] Zheng P,Guo H,Li G,Han S,Luo F,Liu Y.PSMB4 promotes multiple myeloma cell growth by activating NF-κB-miR-21 signaling.Biochem Biophys Res Commun.2015.458(2):328-33. [43] GAO Y,HOU Q,GUO R,et al.Effect of Sun exposure-induced ferroptosis mechanisms on pathology and potential biological processes of primary melanoma by microarray data analysis[J].Front Genet,2022,13:998792. [44] WU C,CHEN J,LIU Y,et al.Upregulation of PSMB4 is Associated with the Necroptosis after Spinal Cord Injury[J].Neurochem Res,2016,41(11):3103-3112. [45] 左卓.转录因子NFE2L1在砷致棕色脂肪细胞分化及活化障碍中的作用及机制研究[D],2022. [46] MA J,LIU S,WANG Y.MicroRNA-21 and multiple myeloma:small molecule and big function[J].Med Oncol,2014,31(8):94. [47] ZHUANG F,LIU Z T,ZHOU G,et al.Integrinβ3-mediated platelet extracellular vesicle adhesion facilitates vascular smooth muscle cell dysfunction in postinjury intimal hyperplasia[J].Int J Biol Sci,2025,21(6):2380-2395. [48] BOCKORNY B,MUTHUSWAMY L,HUANG L,et al.A Large-Scale Proteomics Resource of Circulating Extracellular Vesicles for Biomarker Discovery in Pancreatic Cancer[J].medRxiv,2024:2023.03.13.23287216[pii]. [49] CAMPO C,DA SILVA FILHO M I,WEINHOLD N,et al.Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy: Replication of the Reported Candidate Susceptibility Loci[J].Neurochem Res,2017,42(3):925-931. [50] Adams J.The proteasome:a suitable antineoplastic target.Nat Rev Cancer.2004.4(5):349-60. [51] YANG C H,HSU C F,LAI X Q,et al.Cellular PSMB4 Protein Suppresses Influenza A Virus Replication through Targeting NS1 Protein[J].Viruses,2022,14(10):2277. [52] ROSSI F,EVSTAFIEVA A,PEDRALI-NOY G,et al.HsN3 proteasomal subunit as a target for human immunodeficiency virus type 1 Nef protein[J].Virology,1997,237(1):33-45. [53] CHEN B,CHEN Y,HE Z,et al.S146 and M148 within the mature chain domain of PSMB4 are crucial for degrading PRRSV nsp1α[J].Cell Mol Life Sci,2025,82(1):148. [54] XU G,JIANG X,JAFFREY S R.A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition[J].J Biol Chem,2013,288(41):29573-29585. [55] GONG B,XIAO C,FENG Y,et al.NEK4:prediction of available drug targets and common genetic linkages in bipolar disorder and major depressive disorder[J].Front Psychiatry,2025,16:1414015. [56] WONG M L,DONG C,MAESTRE-MESA J,et al.Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response[J].Mol Psychiatry,2008,13(8):800-812. [57] QURESHI N,PERERA P Y,SHEN J,et al.The proteasome as a lipopolysaccharide-binding protein in macrophages:differential effects of proteasome inhibition on lipopolysaccharide-induced signaling events[J].J Immunol,2003,171(3):1515-1525.

点击下载PDF