维基百科

组织蛋白酶S

位於1號人類染色體的基因

组织蛋白酶S（英文：Cathepsin S）是人类体内由CTSS基因编码的蛋白质[6]。该基因存在利用多腺苷酸化信号的转录变体。[6]

组织蛋白酶S
已知的结构
PDB直系同源搜索: PDBe RCSB
识别号
别名CTSS；, cathepsin S
外部IDOMIM：116845 MGI：107341 HomoloGene：20867 GeneCards：CTSS
为以下药物的标靶
odanacatib[1]
基因位置（人类）
1号染色体
染色体1号染色体[2]
1号染色体
组织蛋白酶S的基因位置
组织蛋白酶S的基因位置
基因座1q21.3起始150,730,079 bp[2]
终止150,765,957 bp[2]
RNA表达模式


查阅更多表达数据
直系同源
物种人类小鼠
Entrez

1520

13040

Ensembl

ENSG00000163131

ENSMUSG00000038642

UniProt

P25774

O70370

mRNA​序列

NM_004079
​NM_001199739

NM_001267695
​NM_021281

蛋白序列

NP_001186668
​NP_004070

NP_001254624
​NP_067256

基因位置​（UCSC）Chr 1: 150.73 – 150.77 MbChr 3: 95.43 – 95.46 Mb
PubMed​查找[4][5]
维基数据
查看/编辑人类查看/编辑小鼠

组织蛋白酶S是木瓜样蛋白酶（英语：Papain-like protease）肽酶C1家族的成员[7]。它是一种溶酶体半胱氨酸蛋白酶，可参与将抗原蛋白降解为肽以呈递给MHC II类分子。[8][9]组织蛋白酶S可以在肺泡巨噬细胞的广泛的pH值范围内作为弹性蛋白酶发挥作用。[10][11]

作用

虽然人们早已知道组织蛋白酶S在抗原呈递中的作用[12][13]，但现在更加深入地了解到组织蛋白酶S在瘙痒和疼痛或伤害感受中起地作用。[14] 伤害性活性是由组织蛋白酶S通过激活G蛋白偶联受体家族的蛋白酶激活受体（英语：Protease-activated receptor）2和4作为信号分子而产生的。[15]

组织蛋白酶S由抗原呈递细胞表达，包括巨噬细胞、B细胞、树突状细胞和小胶质细胞。[16][17]组织蛋白酶S也由一些上皮细胞表达。[18]在用γ-干扰素刺激后，它在人角质形成细胞中的表达有着显着的增加，并且由于促炎性细胞因子的刺激，它在银屑病角质形成细胞中的表达也会升高。[19]相反，皮质胸腺上皮细胞（英语：Cortical thymic epithelial cells）不表达组织蛋白酶S。[20][21]

虽然许多溶酶体蛋白酶最适合的pH值是酸性的[22][23][24]，但组织蛋白酶S是一个例外。组织蛋白酶S在中性pH值下保持催化活性，而pH值5.0到7.5之间是组织蛋白酶S的最佳pH值范围。[25][26]由于稳定性问题，许多溶酶体蛋白酶被困在溶酶体内。相反，组织蛋白酶S可以保持稳定并在溶酶体外具有生理作用。[27][28]包括巨噬细胞和小胶质细胞在内的免疫细胞会分泌组织蛋白酶S以响应炎症介质，包括脂多糖[29]、促炎性细胞因子[30]和中性粒细胞。[31]在体外，组织蛋白酶S在3M尿素存在下可以保留一些酶活性。[32]组织蛋白酶S作为酶原产生并通过加工被激活。[33]

组织蛋白酶S的活性受到其内源性抑制剂——胱抑素C的严格调节，胱抑素C在抗原呈递中也有作用。[34][35]与胱抑素C相比，胱抑素A和胱抑素B的活性较低。[36]

组织蛋白酶S的活性切割位点 -(-Val-Val-Arg-)- 应该有至少两个氨基酸从每一侧包围它。[37]

在抗原呈现中的作用

组织蛋白酶S在抗原呈现中起关键作用。MHC II类分子与小肽片段相互作用，以在抗原呈现免疫细胞表面呈递。组织蛋白酶S参与阻止抗原加载到复合物中的恒定链（英语：CD74）（li chain）的降解。这种降解发生在溶酶体中。按时间顺序，组织蛋白酶S的作用遵循着天冬氨酸蛋白酶进行的两次切割。组织蛋白酶S切割Ii的残余片段（IiP1）并留下一小部分碎片，称为CLIP。它与复合物有直接的联系。

Ii的蛋白水解很重要，因为它有助于CLIP从MHC II上解离，以便复合物得以加载选定的抗原。加载抗原后，MHC II分子移动到细胞表面。因此，我们可以推测组织蛋白酶S的过度表达可能会导致Ii的过早降解、MHC II的临时加载和自身的免疫攻击。相反，组织蛋白酶S的抑制将导致Ii的降解、将抗原加载到MHC II中的延迟以及在细胞表面上MHC II中未切割li的片段的不适当存在，并且它会削弱免疫反应。例如，这种MHC II不会非常有效地诱导T细胞的增殖。

在巨噬细胞中，组织蛋白酶S可以被组织蛋白酶F取代。

在细胞外基质降解中的作用

分泌出来的组织蛋白酶S会切割一些细胞外基质（ECM）蛋白。组织蛋白酶S被认为是已知最有效的弹性蛋白酶。组织蛋白酶S底物列表包括层粘连蛋白、纤连蛋白、弹性蛋白、骨钙蛋白和一些胶原蛋白。它还切割基底膜的硫酸软骨素、硫酸乙酰肝素和蛋白聚糖。组织蛋白酶S由于其弹性溶解和胶原溶解活性而在血管通透性（英语：Vascular permeability）和血管新生中发挥积极作用。例如，组织蛋白酶S对层粘连蛋白5的切割会导致促血管生成肽。组织蛋白酶S的表达可由肿瘤细胞分泌的促炎因子触发。

在癌变中，组织蛋白酶S会促进肿瘤生长。

在细胞因子调节中的作用

组织蛋白酶S的表达和活性也在银屑病患者的皮肤中被上调。它是否在引起银屑病具有明确的作用尚不清楚，但在同一项研究中，它被证明可以特别切割和激活银屑病相关的促炎细胞因子IL-36γ（英语：IL36G）[30]

伤害感受

组织蛋白酶S在伤害感受（英语：Nociception）中起作用，包括瘙痒和胃肠道疼痛。组织蛋白酶S导致瘙痒和疼痛的机制与蛋白酶激活受体2（英语：Protease-activated receptor 2）和4的能力一致。[38][39]

组织蛋白酶S抑制剂

组织蛋白酶S的合成抑制剂参与了许多针对包括类风湿性关节炎在内的免疫疾病的临床前研究。目前，他们中至少有一个参与了银屑病的临床试验。LHVS（吗啉脲-亮氨酸-高苯丙氨酸-乙烯基砜-苯基）是研究最广泛的组织蛋白酶S的合成抑制剂。LHVS的半抑制浓度（英语：IC50）约为5nM。 LHVS对组织蛋白酶S的抑制作用已被证明。它在创伤性脑损伤后具有神经保护作用。[40]商业抑制剂清单还包括紫斑肽（乙酰-Leu-Val-CHO）和其他抑制剂。

临床意义

组织蛋白酶S已被证明是IV型星形细胞瘤（英语：Astrocytoma）（胶质母细胞瘤）患者的重要预后因素，其抑制作用显示患者平均存活时间延长了5个月。这是因为半胱氨酸酶不能再与其他蛋白酶一起作用来分解脑细胞外基质。这样肿瘤的扩散就停止了。科学家们宣布，这种酶可能可以预测死亡，因为它已被证明与心脏病和癌症有关。

参见

参考文献

  1. ^ 對Cathepsin S起作用的藥物；在維基數據上查看/編輯參考. 
  2. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000163131 - Ensembl, May 2017
  3. ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000038642 - Ensembl, May 2017
  4. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  6. ^ 6.0 6.1 Entrez Gene: CTSS cathepsin S. 
  7. ^ Wang GH, He SW, Du X, Xie B, Gu QQ, Zhang M, Hu YH. Characterization, expression, enzymatic activity, and functional identification of cathepsin S from black rockfish Sebastes schlegelii. Fish & Shellfish Immunology. October 2019, 93: 623–630. PMID 31400512. S2CID 199527780. doi:10.1016/j.fsi.2019.08.012. 
  8. ^ Cheng XW, Zhang J, Song H, Yang G, Qin XZ, Guan LK, et al. [Association between lysosomal cysteine protease cathepsin's activation and left ventricular function and remodeling in hypertensive heart failure rats]. Zhonghua Xin Xue Guan Bing Za Zhi. January 2008, 36 (1): 51–56 [2022-11-01]. PMID 19099930. （原始内容存档于2022-10-01）. 
  9. ^ Chen SJ, Chen LH, Yeh YM, Lin CK, Lin PC, Huang HW, et al. Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy. Theranostics. 2021, 11 (10): 4672–4687. PMC 7978314  . PMID 33754020. doi:10.7150/thno.54793. 
  10. ^ Shi GP, Munger JS, Meara JP, Rich DH, Chapman HA. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. The Journal of Biological Chemistry. April 1992, 267 (11): 7258–7262. PMID 1373132. doi:10.1016/S0021-9258(18)42513-6  . 
  11. ^ Tanaka H, Yamaguchi E, Asai N, Yokoi T, Nishimura M, Nakao H, et al. Cathepsin S, a new serum biomarker of sarcoidosis discovered by transcriptome analysis of alveolar macrophages. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 2019, 36 (2): 141–147. PMC 7247107  . PMID 32476947. doi:10.36141/svdld.v36i2.7620. 
  12. ^ Liu W, Spero DM. Cysteine protease cathepsin S as a key step in antigen presentation. Drug News & Perspectives. July 2004, 17 (6): 357–363. PMID 15334187. doi:10.1358/dnp.2004.17.6.829027. 
  13. ^ Baranov MV, Bianchi F, Schirmacher A, van Aart MA, Maassen S, Muntjewerff EM, et al. The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation. iScience. January 2019, 11: 160–177. Bibcode:2019iSci...11..160B. PMC 6319320  . PMID 30612035. doi:10.1016/j.isci.2018.12.015. 
  14. ^ Tu NH, Inoue K, Chen E, Anderson BM, Sawicki CM, Scheff NN, et al. Cathepsin S Evokes PAR2-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models. Cancers. September 2021, 13 (18): 4697. PMC 8466361  . PMID 34572924. doi:10.3390/cancers13184697  . 
  15. ^ Reddy VB, Sun S, Azimi E, Elmariah SB, Dong X, Lerner EA. Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs. Nature Communications. July 2015, 6: 7864. Bibcode:2015NatCo...6.7864R. PMC 4520244  . PMID 26216096. doi:10.1038/ncomms8864. 
  16. ^ Reich M, Zou F, Sieńczyk M, Oleksyszyn J, Boehm BO, Burster T. Invariant chain processing is independent of cathepsin variation between primary human B cells/dendritic cells and B-lymphoblastoid cells. Cellular Immunology. 2011, 269 (2): 96–103. PMID 21543057. doi:10.1016/j.cellimm.2011.03.012. 
  17. ^ Rupanagudi KV, Kulkarni OP, Lichtnekert J, Darisipudi MN, Mulay SR, Schott B, et al. Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming (PDF). Annals of the Rheumatic Diseases. February 2015, 74 (2): 452–463 [2022-11-02]. PMID 24300027. S2CID 22126353. doi:10.1136/annrheumdis-2013-203717. （原始内容存档 (PDF)于2018-07-19）. 
  18. ^ da Costa AC, Santa-Cruz F, Mattos LA, Rêgo Aquino MA, Martins CR, Bandeira Ferraz ÁA, Figueiredo JL. Cathepsin S as a target in gastric cancer. Molecular and Clinical Oncology. February 2020, 12 (2): 99–103. PMC 6951222  . PMID 31929878. doi:10.3892/mco.2019.1958. 
  19. ^ Schönefuss A, Wendt W, Schattling B, Schulten R, Hoffmann K, Stuecker M, et al. Upregulation of cathepsin S in psoriatic keratinocytes. Experimental Dermatology. August 2010, 19 (8): e80–e88. PMID 19849712. S2CID 31731844. doi:10.1111/j.1600-0625.2009.00990.x. 
  20. ^ Kiuchi S, Tomaru U, Ishizu A, Imagawa M, Kiuchi T, Iwasaki S, et al. Expression of cathepsins V and S in thymic epithelial tumors. Human Pathology. February 2017, 60: 66–74. PMID 27771373. doi:10.1016/j.humpath.2016.09.027. 
  21. ^ Beers C, Burich A, Kleijmeer MJ, Griffith JM, Wong P, Rudensky AY. Cathepsin S controls MHC class II-mediated antigen presentation by epithelial cells in vivo. Journal of Immunology. February 2005, 174 (3): 1205–1212. PMID 15661874. S2CID 30821915. doi:10.4049/jimmunol.174.3.1205. 
  22. ^ Wilkinson RD, Williams R, Scott CJ, Burden RE. Cathepsin S: therapeutic, diagnostic, and prognostic potential. Biological Chemistry. August 2015, 396 (8): 867–882. PMID 25872877. S2CID 17582321. doi:10.1515/hsz-2015-0114. 
  23. ^ Liuzzo JP, Petanceska SS, Devi LA. Neurotrophic factors regulate cathepsin S in macrophages and microglia: A role in the degradation of myelin basic protein and amyloid beta peptide. Molecular Medicine. May 1999, 5 (5): 334–343. PMC 2230424  . PMID 10390549. doi:10.1007/BF03402069. 
  24. ^ Sena BF, Figueiredo JL, Aikawa E. Cathepsin S As an Inhibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease. Frontiers in Cardiovascular Medicine. 2017, 4: 88. PMC 5770806  . PMID 29379789. doi:10.3389/fcvm.2017.00088  . 
  25. ^ Kim NY, Ahn SJ, Lee AR, Seo JS, Kim MS, Kim JK, et al. Cloning, expression analysis and enzymatic characterization of cathepsin S from olive flounder (Paralichthys olivaceus). Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. November 2010, 157 (3): 238–247. PMID 20601061. doi:10.1016/j.cbpb.2010.06.008. 
  26. ^ Brömme D, Bonneau PR, Lachance P, Wiederanders B, Kirschke H, Peters C, et al. Functional expression of human cathepsin S in Saccharomyces cerevisiae. Purification and characterization of the recombinant enzyme. The Journal of Biological Chemistry. March 1993, 268 (7): 4832–4838. PMID 8444861. doi:10.1016/S0021-9258(18)53472-4  . 
  27. ^ Karimkhanloo H, Keenan SN, Sun EW, Wattchow DA, Keating DJ, Montgomery MK, Watt MJ. Circulating cathepsin S improves glycaemic control in mice. The Journal of Endocrinology. February 2021, 248 (2): 167–179. PMID 33289685. S2CID 227951644. doi:10.1530/JOE-20-0408. 
  28. ^ Bibli SI, Hu J, Sigala F, Wittig I, Heidler J, Zukunft S, et al. Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. Circulation. January 2019, 139 (1): 101–114. PMID 29970364. S2CID 49652298. doi:10.1161/CIRCULATIONAHA.118.034757. 
  29. ^ Janga H, Cassidy L, Wang F, Spengler D, Oestern-Fitschen S, Krause MF, et al. Site-specific and endothelial-mediated dysfunction of the alveolar-capillary barrier in response to lipopolysaccharides. Journal of Cellular and Molecular Medicine. February 2018, 22 (2): 982–998. PMC 5783864  . PMID 29210175. doi:10.1111/jcmm.13421. 
  30. ^ 30.0 30.1 Ainscough JS, Macleod T, McGonagle D, Brakefield R, Baron JM, Alase A, et al. Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ. Proceedings of the National Academy of Sciences of the United States of America. March 2017, 114 (13): E2748–E2757. Bibcode:2017PNAS..114E2748A. PMC 5380102  . PMID 28289191. doi:10.1073/pnas.1620954114  . 
  31. ^ Wang H, Jiang H, Cheng XW. Cathepsin S are involved in human carotid atherosclerotic disease progression, mainly by mediating phagosomes: bioinformatics and in vivo and vitro experiments. PeerJ. 2022, 10: e12846. PMC 8833225  . PMID 35186462. doi:10.7717/peerj.12846. 
  32. ^ Flynn CM, Garbers Y, Düsterhöft S, Wichert R, Lokau J, Lehmann CH, et al. Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro. Scientific Reports. December 2020, 10 (1): 21612. Bibcode:2020NatSR..1021612F. PMC 7730449  . PMID 33303781. doi:10.1038/s41598-020-77884-4. 
  33. ^ Wiederanders B. The function of propeptide domains of cysteine proteinases. Advances in Experimental Medicine and Biology. 2000, 477: 261–270. ISBN 0-306-46383-0. PMID 10849753. doi:10.1007/0-306-46826-3_28. 
  34. ^ Paraoan L, Gray D, Hiscott P, Garcia-Finana M, Lane B, Damato B, Grierson I. Cathepsin S and its inhibitor cystatin C: imbalance in uveal melanoma. Frontiers in Bioscience. January 2009, 14 (7): 2504–2513. PMID 19273215. doi:10.2741/3393. 
  35. ^ Zhang W, Zi M, Sun L, Wang F, Chen S, Zhao Y, et al. Cystatin C regulates major histocompatibility complex-II-peptide presentation and extracellular signal-regulated kinase-dependent polarizing cytokine production by bone marrow-derived dendritic cells. Immunology and Cell Biology. November 2019, 97 (10): 916–930. PMID 31513306. S2CID 213168319. doi:10.1111/imcb.12290. 
  36. ^ Bangsuwan P, Hirunwidchayarat W, Jirawechwongsakul P, Talungchit S, Taebunpakul P. Expression of Cathepsin B and Cystatin A in Oral Lichen Planus. Journal of International Society of Preventive & Community Dentistry. September 2021, 11 (5): 566–573. PMC 8533036  . PMID 34760802. doi:10.4103/jispcd.JISPCD_97_21 (不活跃 2022-10-07). 
  37. ^ Fu Q, Zhao S, Yang N, Tian M, Cai X, Zhang L, et al. Genome-wide identification, expression signature and immune functional analysis of two cathepsin S (CTSS) genes in turbot (Scophthalmus maximus L.). Fish & Shellfish Immunology. July 2020, 102: 243–256. PMID 32315741. S2CID 216074706. doi:10.1016/j.fsi.2020.04.028. 
  38. ^ Elmariah SB, Reddy VB, Lerner EA. Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist. PLOS ONE. June 25, 2014, 9 (6): e99702. Bibcode:2014PLoSO...999702E. PMC 4070910  . PMID 24964046. doi:10.1371/journal.pone.0099702  . 
  39. ^ Reddy VB, Sun S, Azimi E, Elmariah SB, Dong X, Lerner EA. Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs. Nature Communications. July 2015, 6: 7864. Bibcode:2015NatCo...6.7864R. PMC 4520244  . PMID 26216096. doi:10.1038/ncomms8864. 
  40. ^ Xu J, Wang H, Ding K, Lu X, Li T, Wang J, et al. Inhibition of cathepsin S produces neuroprotective effects after traumatic brain injury in mice. Mediators of Inflammation. Oct 24, 2013, 2013 (2013): 187873. PMC 3824312  . PMID 24282339. doi:10.1155/2013/187873  . 

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外部链接

检索自“https://zh.wikipedia.org/w/index.php?title=组织蛋白酶S&oldid=85358439”