维基百科

组织蛋白酶B

位於8號人類染色體的基因

组织蛋白酶B（英文：Cathepsin B）属于溶酶体半胱氨酸蛋白酶家族，也叫半胱氨酸组织蛋白酶，在细胞内蛋白水解中起重要作用。[5]在人体内的组织蛋白酶B被编码为CTSB基因。[6][7]组织蛋白酶B的水平在某些癌症、癌前病变和各种其他病理状况中会上调。[8][9][10][11]

组织蛋白酶B
已知的结构
PDB直系同源搜索: PDBe RCSB
识别号
别名CTSB；, APPS, CPSB, cathepsin B, RECEUP
外部IDOMIM：116810 MGI：88561 HomoloGene：37550 GeneCards：CTSB
基因位置（人类）
8号染色体
染色体8号染色体[1]
8号染色体
组织蛋白酶B的基因位置
组织蛋白酶B的基因位置
基因座8p23.1起始11,842,524 bp[1]
终止11,869,448 bp[1]
RNA表达模式




查阅更多表达数据
直系同源
物种人类小鼠
Entrez

1508

13030

Ensembl

ENSG00000164733
​ENSG00000285132

ENSMUSG00000021939

UniProt

P07858

P10605

mRNA​序列

NM_007798

蛋白序列

NP_031824

基因位置​（UCSC）Chr 8: 11.84 – 11.87 MbChr 14: 63.36 – 63.38 Mb
PubMed​查找[3][4]
维基数据
查看/编辑人类查看/编辑小鼠

结构

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基因

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CTSB基因位于染色体8p22，由13个外显子组成。CTSB基因位于8p22染色体，由13个外显子组成。CTSB基因的启动子含有一个富含GC的区域，包含许多SP1位点，类似于管家基因。[12]已发现该基因至少有五个编码相同蛋白质的转录变体。[13]

蛋白质

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组织蛋白酶B在粗面内质网上合成为339个氨基酸的前酶原，具有17个氨基酸的信号肽。[14][15]然后将43/46 kDa的组织蛋白酶原B转运到高尔基体，在那里将形成组织蛋白酶B。成熟的组织蛋白酶B由25-26 kDa的重链和5 kDa的轻链组成，它们通过二硫键的二聚体连接。

功能

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组织蛋白酶B可增强其他蛋白酶的活性，包括基质金属蛋白酶、尿激酶（丝氨酸蛋白酶尿激酶纤溶酶原激活剂）和组织蛋白酶D。[16][17]因此，它在细胞外基质成分的蛋白水解、细胞间通讯中断和减少蛋白酶抑制剂的表达方面具有重要作用。[18]它还参与自噬和分解代谢，有造成肿瘤的恶性发展，并可能参与特异性免疫抵抗。[19]此外，它被确定为具有较小的连接酶活性，能够通过酰胺键连接肽片段。[20]

临床意义

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组织蛋白酶B可以作为多种癌症的潜在有效生物标志物。.[16][21][22][23][24][25] 组织蛋白酶B的过度表达与侵袭性和转移性癌症有关。[26]组织蛋白酶B在新陈代谢过程中在肌肉组织中产生。它能够穿过血脑屏障[27]并且与神经发生有关，特别是在小鼠齿状回中。多种疾病导致组织蛋白酶B水平升高，从而导致许多病理过程，包括细胞死亡、炎症和有毒肽的产生。专注于神经系统疾病，在癫痫啮齿动物模型中的组织蛋白酶 B 基因敲除研究表明，组织蛋白酶B会导致大量因诱发癫痫而发生的凋亡细胞死亡。[28]

对诱发癫痫发作的老鼠进行组织蛋白酶B抑制剂治疗，可改善神经系统评分、学习能力，并大大减少神经元细胞死亡和促凋亡细胞死亡肽。[29]同样，在创伤性脑损伤老鼠模型中组织蛋白酶B基因敲除和组织蛋白酶B抑制剂治疗研究表明，组织蛋白酶B是导致神经肌肉功能障碍、记忆丧失、神经元细胞死亡以及增加促坏死与促凋亡细胞死亡肽的关键。[30][31]在缺血性非人类灵长类动物和啮齿动物模型中，组织蛋白酶B抑制剂治疗可防止脑神经元显着丧失，尤其是在海马体中的神经元。[32][33][34]在肺炎链球菌脑膜炎啮齿动物模型中，组织蛋白酶B抑制剂治疗极大地改善了感染的临床过程，并减少了脑部炎症和炎症性白细胞介素-1β （IL1-β）和肿瘤坏死因子-α（TNF-α）。[35]

在表达人类前类淀粉蛋白质（APP）的转基因阿尔茨海默症动物模型中，该模型含有在大多数阿尔茨海默症患者或豚鼠中发现的野生型β-分泌酶位点序列，这是人类野生型APP加工的自然模型, 遗传上删除组织蛋白酶B基因或化学上抑制组织蛋白酶B大脑活动导致此类小鼠的记忆缺陷得到显着改善并降低神经毒性全长β淀粉样蛋白(1-40/42)和特别有害的焦谷氨酸β淀粉样蛋白的水平(3-40/42)，这被认为是导致疾病的原因。[36][37][38][39][40][41][42]在一个非转基的因衰老加速的小鼠品系中，它也具有含有野生型β-分泌酶位点序列的APP，用银杏叶提取出的白果内酯，也可以通过组织蛋白酶B抑制剂降低了β淀粉样蛋白。[43]此外，siRNA 沉默或化学抑制具有人类野生型 β-分泌酶活性的原代啮齿动物海马细胞或牛嗜铬细胞中的组织蛋白酶B，可通过调节分泌途径减少β淀粉样蛋白的分泌。[44][45]CTSB基因的突变与热带胰腺炎（一种慢性胰腺炎）有关。[46]

相互作用

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组织蛋白酶B可以与以下物质产生相互作用：

组织蛋白酶B可以被以下物质抑制：

参见

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参考文献

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  1. ^ 1.0 1.1 1.2 GRCh38: Ensembl release 89: ENSG00000164733、​ENSG00000285132 - Ensembl, May 2017
  2. ^ 2.0 2.1 2.2 GRCm38: Ensembl release 89: ENSMUSG00000021939 - Ensembl, May 2017
  3. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  4. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Sloane BF. Cathepsin B and cystatins: evidence for a role in cancer progression. Seminars in Cancer Biology. April 1990, 1 (2): 137–52. PMID 2103490. 
  6. ^ Chan SJ, San Segundo B, McCormick MB, Steiner DF. Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs. Proceedings of the National Academy of Sciences of the United States of America. October 1986, 83 (20): 7721–5. Bibcode:1986PNAS...83.7721C. PMC 386793  . PMID 3463996. doi:10.1073/pnas.83.20.7721  . 
  7. ^ Cao L, Taggart RT, Berquin IM, Moin K, Fong D, Sloane BF. Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene. Gene. February 1994, 139 (2): 163–9. PMID 8112600. doi:10.1016/0378-1119(94)90750-1. 
  8. ^ Tong B, Wan B, Wei Z, Wang T, Zhao P, Dou Y, Lv Z, Xia Y, Dai Y. Role of cathepsin B in regulating migration and invasion of fibroblast-like synoviocytes into inflamed tissue from patients with rheumatoid arthritis. Clinical and Experimental Immunology. September 2014, 177 (3): 586–97. PMC 4137842  . PMID 24749816. doi:10.1111/cei.12357. 
  9. ^ Lai WF, Chang CH, Tang Y, Bronson R, Tung CH. Early diagnosis of osteoarthritis using cathepsin B sensitive near-infrared fluorescent probes. Osteoarthritis and Cartilage. March 2004, 12 (3): 239–44. PMID 14972341. doi:10.1016/j.joca.2003.11.005  . 
  10. ^ Ha SD, Ham B, Mogridge J, Saftig P, Lin S, Kim SO. Cathepsin B-mediated autophagy flux facilitates the anthrax toxin receptor 2-mediated delivery of anthrax lethal factor into the cytoplasm. The Journal of Biological Chemistry. January 2010, 285 (3): 2120–9. PMC 2804368  . PMID 19858192. doi:10.1074/jbc.M109.065813  . 
  11. ^ Yang WE, Ho CC, Yang SF, Lin SH, Yeh KT, Lin CW, Chen MK. Cathepsin B Expression and the Correlation with Clinical Aspects of Oral Squamous Cell Carcinoma. PLOS ONE. 2016, 11 (3): e0152165. Bibcode:2016PLoSO..1152165Y. PMC 4816521  . PMID 27031837. doi:10.1371/journal.pone.0152165  . 
  12. ^ Qian F, Frankfater A, Chan SJ, Steiner DF. The structure of the mouse cathepsin B gene and its putative promoter. DNA and Cell Biology. April 1991, 10 (3): 159–68. PMID 2012677. doi:10.1089/dna.1991.10.159. 
  13. ^ Entrez Gene: CTSB cathepsin B. 
  14. ^ Kirschke H, Barrett AJ, Rawlings ND. Proteinases 1: lysosomal cysteine proteinases. Protein Profile. 1995, 2 (14): 1581–643. PMID 8771190. 
  15. ^ Mort JS, Buttle DJ. Cathepsin B. The International Journal of Biochemistry & Cell Biology. May 1997, 29 (5): 715–20. PMID 9251238. doi:10.1016/s1357-2725(96)00152-5. 
  16. ^ 16.0 16.1 Alapati K, Kesanakurti D, Rao JS, Dasari VR. uPAR and cathepsin B-mediated compartmentalization of JNK regulates the migration of glioma-initiating cells. Stem Cell Research. May 2014, 12 (3): 716–29. PMC 4061617  . PMID 24699410. doi:10.1016/j.scr.2014.02.008. 
  17. ^ Vigneswaran N, Zhao W, Dassanayake A, Muller S, Miller DM, Zacharias W. Variable expression of cathepsin B and D correlates with highly invasive and metastatic phenotype of oral cancer. Human Pathology. August 2000, 31 (8): 931–7. PMID 10987253. doi:10.1053/hupa.2000.9035. 
  18. ^ Yang, Wei-En; Ho, Chuan-Chen; Yang, Shun-Fa; Lin, Shu-Hui; Yeh, Kun-Tu; Lin, Chiao-Wen; Chen, Mu-Kuan. Cathepsin B Expression and the Correlation with Clinical Aspects of Oral Squamous Cell Carcinoma. PLoS ONE. 2016-03-31, 11 (3) [2022-09-12]. ISSN 1932-6203. PMC 4816521  . PMID 27031837. doi:10.1371/journal.pone.0152165. （原始内容存档于2022-09-12）. 
  19. ^ Fais S. Cannibalism: a way to feed on metastatic tumors. Cancer Letters. December 2007, 258 (2): 155–64. PMID 17977647. doi:10.1016/j.canlet.2007.09.014. 
  20. ^ Lambeth, Tyler R.; Dai, Zhefu; Zhang, Yong; Julian, Ryan R. A two-trick pony: lysosomal protease cathepsin B possesses surprising ligase activity. RSC Chemical Biology. 2021, 2 (2): 606–611. ISSN 2633-0679. PMC 8291735  . PMID 34291207. doi:10.1039/D0CB00224K   （英语）. 
  21. ^ Mirković B, Markelc B, Butinar M, Mitrović A, Sosič I, Gobec S, Vasiljeva O, Turk B, Čemažar M, Serša G, Kos J. Nitroxoline impairs tumor progression in vitro and in vivo by regulating cathepsin B activity. Oncotarget. August 2015, 6 (22): 19027–42. PMC 4662473  . PMID 25848918. doi:10.18632/oncotarget.3699. 
  22. ^ Bian B, Mongrain S, Cagnol S, Langlois MJ, Boulanger J, Bernatchez G, Carrier JC, Boudreau F, Rivard N. Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis. Molecular Carcinogenesis. May 2016, 55 (5): 671–87. PMC 4832390  . PMID 25808857. doi:10.1002/mc.22312. 
  23. ^ Bengsch F, Buck A, Günther SC, Seiz JR, Tacke M, Pfeifer D, von Elverfeldt D, Sevenich L, Hillebrand LE, Kern U, Sameni M, Peters C, Sloane BF, Reinheckel T. Cell type-dependent pathogenic functions of overexpressed human cathepsin B in murine breast cancer progression. Oncogene. September 2014, 33 (36): 4474–84. PMC 4139469  . PMID 24077280. doi:10.1038/onc.2013.395. 
  24. ^ Bao W, Fan Q, Luo X, Cheng WW, Wang YD, Li ZN, Chen XL, Wu D. Silencing of Cathepsin B suppresses the proliferation and invasion of endometrial cancer. Oncology Reports. August 2013, 30 (2): 723–30. PMID 23708264. doi:10.3892/or.2013.2496  . 
  25. ^ Yin M, Soikkeli J, Jahkola T, Virolainen S, Saksela O, Hölttä E. TGF-β signaling, activated stromal fibroblasts, and cysteine cathepsins B and L drive the invasive growth of human melanoma cells. The American Journal of Pathology. December 2012, 181 (6): 2202–16. PMID 23063511. doi:10.1016/j.ajpath.2012.08.027  . 
  26. ^ Ruan J, Zheng H, Rong X, Rong X, Zhang J, Fang W, Zhao P, Luo R. Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients. Molecular Cancer. 20 February 2016, 15: 17. PMC 4761221  . PMID 26896959. doi:10.1186/s12943-016-0503-9. 
  27. ^ Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA, Duzel E, van Praag H. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function. Cell Metabolism. June 2016, 24 (2): 332–40. PMC 6029441  . PMID 27345423. doi:10.1016/j.cmet.2016.05.025. 
  28. ^ Houseweart MK, Pennacchio LA, Vilaythong A, Peters C, Noebels JL, Myers RM. Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1). Journal of Neurobiology. September 2003, 56 (4): 315–27. PMID 12918016. doi:10.1002/neu.10253. 
  29. ^ Ni H, Ren SY, Zhang LL, Sun Q, Tian T, Feng X. Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus. Toxicology Letters. February 2013, 217 (2): 162–9. PMID 23266720. doi:10.1016/j.toxlet.2012.12.010. 
  30. ^ Hook GR, Yu J, Sipes N, Pierschbacher MD, Hook V, Kindy MS. The cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury. Journal of Neurotrauma. March 2014, 31 (5): 515–29. PMC 3934599  . PMID 24083575. doi:10.1089/neu.2013.2944. 
  31. ^ Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ, Cao QQ, Ni H, Qin ZH, Tao LY. Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway. Journal of Neuroscience Research. October 2010, 88 (13): 2847–58. PMID 20653046. S2CID 2977933. doi:10.1002/jnr.22453. 
  32. ^ Yoshida M, Yamashima T, Zhao L, Tsuchiya K, Kohda Y, Tonchev AB, Matsuda M, Kominami E. Primate neurons show different vulnerability to transient ischemia and response to cathepsin inhibition. Acta Neuropathologica. September 2002, 104 (3): 267–72. PMID 12172912. S2CID 10913622. doi:10.1007/s00401-002-0554-4. 
  33. ^ Tsuchiya K, Kohda Y, Yoshida M, Zhao L, Ueno T, Yamashita J, Yoshioka T, Kominami E, Yamashima T. Postictal blockade of ischemic hippocampal neuronal death in primates using selective cathepsin inhibitors. Experimental Neurology. February 1999, 155 (2): 187–94. PMID 10072294. S2CID 22548769. doi:10.1006/exnr.1998.6988. 
  34. ^ Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH. Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats. Journal of Neuroscience Research. September 2006, 84 (4): 832–40. PMID 16802320. S2CID 24194809. doi:10.1002/jnr.20977. 
  35. ^ Hoegen T, Tremel N, Klein M, Angele B, Wagner H, Kirschning C, Pfister HW, Fontana A, Hammerschmidt S, Koedel U. The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release. Journal of Immunology. November 2011, 187 (10): 5440–51. PMID 22003197. doi:10.4049/jimmunol.1100790  . 
  36. ^ Hook VY, Kindy M, Hook G. Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. The Journal of Biological Chemistry. March 2008, 283 (12): 7745–53. PMID 18184658. doi:10.1074/jbc.m708362200  . 
  37. ^ Hook V, Kindy M, Hook G. Cysteine protease inhibitors effectively reduce in vivo levels of brain beta-amyloid related to Alzheimer's disease. Biological Chemistry. February 2007, 388 (2): 247–52. PMID 17261088. S2CID 34617103. doi:10.1515/bc.2007.027. 
  38. ^ Hook G, Hook VY, Kindy M. Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer's disease therapeutics. Biological Chemistry. September 2007, 388 (9): 979–83. PMID 17696783. S2CID 84162059. doi:10.1515/BC.2007.117. 
  39. ^ Hook VY, Kindy M, Reinheckel T, Peters C, Hook G. Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein. Biochemical and Biophysical Research Communications. August 2009, 386 (2): 284–8. PMC 2753505  . PMID 19501042. doi:10.1016/j.bbrc.2009.05.131. 
  40. ^ Hook G, Hook V, Kindy M. The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity. Journal of Alzheimer's Disease. 2011, 26 (2): 387–408. PMC 4317342  . PMID 21613740. doi:10.3233/JAD-2011-110101. 
  41. ^ Kindy MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR. Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. Journal of Alzheimer's Disease. 2012, 29 (4): 827–40. PMC 4309289  . PMID 22337825. doi:10.3233/JAD-2012-111604. 
  42. ^ Hook G, Yu J, Toneff T, Kindy M, Hook V. Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. Journal of Alzheimer's Disease. 2014, 41 (1): 129–49. PMC 4059604  . PMID 24595198. doi:10.3233/JAD-131370. 
  43. ^ Shi C, Zheng DD, Wu FM, Liu J, Xu J. The phosphatidyl inositol 3 kinase-glycogen synthase kinase 3β pathway mediates bilobalide-induced reduction in amyloid β-peptide. Neurochemical Research. February 2012, 37 (2): 298–306. PMID 21952928. S2CID 5744771. doi:10.1007/s11064-011-0612-1. 
  44. ^ Hook V, Toneff T, Bogyo M, Greenbaum D, Medzihradszky KF, Neveu J, Lane W, Hook G, Reisine T. Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer's disease. Biological Chemistry. September 2005, 386 (9): 931–40. PMID 16164418. S2CID 9038695. doi:10.1515/BC.2005.108. 
  45. ^ Klein DM, Felsenstein KM, Brenneman DE. Cathepsins B and L differentially regulate amyloid precursor protein processing. The Journal of Pharmacology and Experimental Therapeutics. March 2009, 328 (3): 813–21. PMID 19064719. S2CID 7798381. doi:10.1124/jpet.108.147082. 
  46. ^ Tandon RK. Tropical pancreatitis. Journal of Gastroenterology. January 2007,. 42 Suppl 17 (Suppl 17): 141–7. PMID 17238044. S2CID 2796833. doi:10.1007/s00535-006-1930-y. 
  47. ^ van der Stappen JW, Williams AC, Maciewicz RA, Paraskeva C. Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D. International Journal of Cancer. August 1996, 67 (4): 547–54. PMID 8759615. doi:10.1002/(SICI)1097-0215(19960807)67:4<547::AID-IJC14>3.0.CO;2-4  . 
  48. ^ 48.0 48.1 Pavlova A, Björk I. Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases. Biochemistry. September 2003, 42 (38): 11326–33. PMID 14503883. doi:10.1021/bi030119v. 
  49. ^ Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I. The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L. Biochemistry. May 1998, 37 (20): 7551–60. PMID 9585570. doi:10.1021/bi980026r. 
  50. ^ Pol E, Björk I. Role of the single cysteine residue, Cys 3, of human and bovine cystatin B (stefin B) in the inhibition of cysteine proteinases. Protein Science. September 2001, 10 (9): 1729–38. PMC 2253190  . PMID 11514663. doi:10.1110/ps.11901. 
  51. ^ Mai J, Finley RL, Waisman DM, Sloane BF. Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells. The Journal of Biological Chemistry. April 2000, 275 (17): 12806–12. PMID 10777578. doi:10.1074/jbc.275.17.12806  . 
  52. ^ Hurley EA, Thorley-Lawson DA. B cell activation and the establishment of Epstein-Barr virus latency. The Journal of Experimental Medicine. December 1988, 168 (6): 2059–75. PMC 2189139  . PMID 2848918. doi:10.1084/jem.168.6.2059. 
  53. ^ Murata, Mitsuo; Miyashita, Satsuki; Yokoo, Chihiro; Tamai, Musaharu; Hanada, Kazunori; Hatayama, Katsuo; Towatari, Takae; Nikawa, Takeshi; Katunuma, Nobuhiko. Novel epoxysuccinyl peptides Selective inhibitors of cathepsin B, in vitro. FEBS Letters. 1991-03-25, 280 (2). doi:10.1016/0014-5793(91)80318-W （英语）. 
检索自“https://zh.wikipedia.org/w/index.php?title=组织蛋白酶B&oldid=75102762”