胱天蛋白酶8

胱天蛋白酶8（英语：Caspase 8）是一种胱天蛋白酶，由CASP8基因编码。该酶很可能作用于胱天蛋白酶3。许多可获得完整基因组数据的哺乳动物都已鉴定出CASP8直系同源物。^[7]这些独特的直系同源物也存在于鸟类中。

胱天蛋白酶8
已知的结构 PDB 直系同源搜索: PDBe RCSB PDBID列表 1F9E、​1I4E、​1QDU、​1QTN、​2C2Z、​2FUN、​2K7Z、​2Y1L、​3H11、​3KJN、​3KJQ、​4JJ7、​4PRZ、​4PS1、​4ZBW
识别号
别名	CASP8；, ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5, caspase 8
外部ID	OMIM：601763 MGI：1261423 HomoloGene：7657 GeneCards：CASP8
相关疾病
caspase-8 deficiency[1]
为以下药物的标靶
emricasan[2]
基因位置（人类） 染色体 2号染色体[3] 基因座 2q33.1 起始 201,233,443 bp[3] 终止 201,287,711 bp[3]
基因位置（小鼠） 染色体 小鼠1号染色体[4] 基因座 1 C1.3|1 29.19 cM 起始 58,834,533 bp[4] 终止 58,886,662 bp[4]
RNA表达模式
查阅更多表达数据
基因本体 分子功能 • death effector domain binding • 半胱氨酸型肽酶活性 • cysteine-type endopeptidase activity involved in apoptotic signaling pathway • scaffold protein binding • 血浆蛋白结合 • 相同蛋白质结合 • cysteine-type endopeptidase activity involved in apoptotic process • cysteine-type endopeptidase activity • 水解酶活性 • 泛素蛋白连接酶结合 • 肽酶活性 • cysteine-type endopeptidase activity involved in execution phase of apoptosis • death receptor binding • tumor necrosis factor receptor binding • 大分子复合物结合 细胞组分 • cell body • 细胞质基质 • CD95 death-inducing signaling complex • ripoptosome • 核质 • mitochondrial outer membrane • 死亡诱导信号复合体 • 脂筏模型 • neuron projection • 细胞骨架 • 细胞质 • 线粒体 • 细胞核 • 大分子复合体 生物学过程 • regulation of apoptotic process • response to estradiol • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway • response to antibiotic • 肿瘤坏死因子介导的信号通路的调控 • positive regulation of macrophage differentiation • cellular response to organic cyclic compound • natural killer cell activation • negative regulation of I-kappaB kinase/NF-kappaB signaling • TRAIL-activated apoptotic signaling pathway • 蛋白酶解 • macrophage differentiation • TRIF-dependent toll-like receptor signaling pathway • response to tumor necrosis factor • B cell activation • cell surface receptor signaling pathway • response to lipopolysaccharide • cellular response to mechanical stimulus • activation of cysteine-type endopeptidase activity • positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway • death-inducing signaling complex assembly • positive regulation of proteolysis • positive regulation of I-kappaB kinase/NF-kappaB signaling • apoptotic signaling pathway • response to cold • regulation of extrinsic apoptotic signaling pathway via death domain receptors • viral process • response to ethanol • response to cobalt ion • activation of cysteine-type endopeptidase activity involved in apoptotic process • proteolysis involved in cellular protein catabolic process • syncytiotrophoblast cell differentiation involved in labyrinthine layer development • 含有信号通路的核苷酸结合寡聚结构域 • T细胞活化 • suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process • 细胞凋亡 • extrinsic apoptotic signaling pathway • 死亡域受体对外源性凋亡信号通路的负调控 • regulation of necroptotic process • execution phase of apoptosis • toll-like receptor 3 signaling pathway • positive regulation of neuron death • extrinsic apoptotic signaling pathway via death domain receptors • positive regulation of interleukin-1 beta production Sources:Amigo / QuickGO
直系同源
物种	人类	小鼠
Entrez	841	12370
Ensembl	ENSG00000064012	ENSMUSG00000026029
UniProt	Q14790	O89110
mRNA​序列	​NM_001080124 ​NM_001080125 ​NM_001228 ​NM_033355 ​NM_033356 ​NM_033357 ​NM_033358 ​NM_001372051	NM_001080126 ​NM_001277926 ​NM_009812
蛋白序列	NP_001073593 ​NP_001073594 ​NP_001219 ​NP_203519 ​NP_203520 ​NP_203522 ​NP_001358980	NP_001073595 ​NP_001264855 ​NP_033942
基因位置​（UCSC）	Chr 2: 201.23 – 201.29 Mb	Chr 1: 58.83 – 58.89 Mb
PubMed​查找	[5]	[6]
维基数据
查看/编辑人类 查看/编辑小鼠

作用

胱天蛋白酶8是胱天蛋白酶家族的成员。半胱天冬酶的连续激活在细胞凋亡的执行阶段发挥着核心作用。半胱天冬酶作为无活性酶原存在，由前结构域、大蛋白酶亚基和小蛋白酶亚基组成。半胱天冬酶的激活需要在保守的天冬氨酸残基处经历蛋白水解加工，以产生一大一小两个亚基组成的异二聚体酶。该蛋白参与Fas和各种细胞凋亡刺激诱导的程序性细胞死亡。该蛋白的N端FADD样死亡效应结构域表明它可能与FADD相互作用。这种蛋白质在亨廷顿舞蹈症患者受影响的大脑区域的不溶性部分中检测到，而在正常对照的大脑区域中未检测到，这表明它在神经退行性疾病中的作用。已经描述了许多编码不同亚型的选择性剪接转录物变体，尽管并非所有变体都已确定其全长序列。^[8]

临床意义

一种非常罕见的免疫系统遗传性疾病也可能是由该基因的突变引起的。这种疾病称为CEDS，意思是“胱天蛋白酶8缺乏状态”。CEDS具有与另一种细胞凋亡遗传病ALPS 相似的特征，但前者有免疫缺陷表型。因此，除了复发性鼻窦及肺部感染、复发性皮肤粘膜疱疹病、持续性疣和传染性软疣感染以及咖玛免疫球蛋白过低之外，临床表现还包括脾肿大和淋巴结肿大。主质器官有时存在淋巴细胞浸润性疾病，但自身免疫性极小，而且在CEDS患者中尚未观察到淋巴瘤。CEDS以常染色体隐性方式遗传。^[9]

CEDS患者的临床表型呈现出一个悖论，因为胱天蛋白酶8被认为主要是一种促凋亡蛋白酶，主要参与肿瘤坏死因子受体家族死亡受体（例如Fas）的信号转导。淋巴细胞激活和保护性免疫的缺陷表明胱天蛋白酶8在淋巴细胞中具有额外的信号传导作用。进一步的研究表明，胱天蛋白酶8在T、B和自然杀伤细胞中，通过抗原受体、Fc受体或 Toll样受体4刺激后，对转录因子“核因子κB”（NF-κB）的诱导至关重要 。^[9]

生化方面，发现胱天蛋白酶8进入NF-κB激酶抑制剂（IKK）与上游Bcl10-MALT1（粘膜相关淋巴组织）适配器复合物的复合体中，这对于诱导NF-κB的核转位至关重要 。此外，胱天蛋白酶8的生化形式在这两种途径中是不同的。对于死亡途径，胱天蛋白酶8酶原被切割成亚基，这些亚基组装形成成熟的、高活性的胱天蛋白酶异四聚体；而对于激活途径，酶原似乎保持完整，可能是为了限制其蛋白水解功能，但增强其作为适配器蛋白的功能。^[9]

相互作用

胱天蛋白酶8已被证明可以与以下物质相互作用：

• BCAP31^[10]
• BID^[11][12]
• Bcl-2^[12][13]
• CFLAR^{[14][15][16][17][18][19][20]}
• 胱天蛋白酶10^{[11][12][14][21]}
• 胱天蛋白酶2^[12][21]
• 胱天蛋白酶3^[12][21]
• 胱天蛋白酶6^[12][21][22]
• 胱天蛋白酶7^[12][21]
• 胱天蛋白酶9^[12][21]
• DEDD^[23][24][25]
• FADD^{[11][14][17][26][27][28][29]}
• FasL^[11][14]
• FasR^[11][15][30]
• IFT57^[31]
• NOL3^[32]
• PEA15^[33][34]
• RIPK1^[26][35][36]
• TNFRSF10B^[11][30]
• TRAF1^[14][37]

附加图片

TNF-R1信号通路。灰色虚线表示多个步骤 细胞凋亡涉及的信号转导途径概述

参见

• 胱天蛋白酶
• FADD
• 蛋白酶解图谱（英语：The Proteolysis Map）

参考文献

1. 與胱天蛋白酶8相關的疾病；在維基數據上查看/編輯參考.
2. 對Caspase 8起作用的藥物；在維基數據上查看/編輯參考.
3. GRCh38: Ensembl release 89: ENSG00000064012 - Ensembl, May 2017
4. GRCm38: Ensembl release 89: ENSMUSG00000026029 - Ensembl, May 2017
5. Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
6. Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
7. OrthoMaM phylogenetic marker: CASP8 coding sequence.^{[永久失效链接]}
8. Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase. [2024-02-05]. （原始内容存档于2009-05-11）.
9. Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002, 419 (6905): 395–9 [2024-02-05]. Bibcode:2002Natur.419..395C. PMID 12353035. S2CID 4359174. doi:10.1038/nature01063. （原始内容存档于2023-03-27）.
10. Ng FW, Nguyen M, Kwan T, Branton PE, Nicholson DW, Cromlish JA, Shore GC. p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum. J. Cell Biol. October 1997, 139 (2): 327–38. PMC 2139787 . PMID 9334338. doi:10.1083/jcb.139.2.327.
11. Gajate C, Mollinedo F. Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J. Biol. Chem. March 2005, 280 (12): 11641–7. PMID 15659383. doi:10.1074/jbc.M411781200 .
12. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES. Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J. Biol. Chem. April 2002, 277 (16): 13430–7. PMID 11832478. doi:10.1074/jbc.M108029200 .
13. Poulaki V, Mitsiades N, Romero ME, Tsokos M. Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2. Cancer Res. June 2001, 61 (12): 4864–72. PMID 11406564.
14. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes (PDF). Cell. July 2003, 114 (2): 181–90 [2024-02-05]. PMID 12887920. S2CID 17145731. doi:10.1016/s0092-8674(03)00521-x. （原始内容存档 (PDF)于2023-01-27）.
15. Shu HB, Halpin DR, Goeddel DV. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity. June 1997, 6 (6): 751–63. PMID 9208847. doi:10.1016/s1074-7613(00)80450-1 .
16. Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM, Wallach D. CASH, a novel caspase homologue with death effector domains. J. Biol. Chem. August 1997, 272 (32): 19641–4. PMID 9289491. doi:10.1074/jbc.272.32.19641 .
17. Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC, Alnemri ES. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J. Biol. Chem. July 1997, 272 (30): 18542–5. PMID 9228018. doi:10.1074/jbc.272.30.18542 .
18. Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grütter MG. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J. Biol. Chem. November 2002, 277 (47): 45162–71. PMID 12215447. doi:10.1074/jbc.M206882200 .
19. Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, Baskin DG, Schwartz SM, Hood L. MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death. Proc. Natl. Acad. Sci. U.S.A. October 1997, 94 (21): 11333–8. Bibcode:1997PNAS...9411333H. PMC 23459 . PMID 9326610. doi:10.1073/pnas.94.21.11333 .
20. Roth W, Stenner-Liewen F, Pawlowski K, Godzik A, Reed JC. Identification and characterization of DEDD2, a death effector domain-containing protein. J. Biol. Chem. March 2002, 277 (9): 7501–8. PMID 11741985. doi:10.1074/jbc.M110749200 .
21. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc. Natl. Acad. Sci. U.S.A. December 1996, 93 (25): 14486–91. Bibcode:1996PNAS...9314486S. PMC 26159 . PMID 8962078. doi:10.1073/pnas.93.25.14486 .
22. Cowling V, Downward J. Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ. October 2002, 9 (10): 1046–56. PMID 12232792. doi:10.1038/sj.cdd.4401065 .
23. Zhan Y, Hegde R, Srinivasula SM, Fernandes-Alnemri T, Alnemri ES. Death effector domain-containing proteins DEDD and FLAME-3 form nuclear complexes with the TFIIIC102 subunit of human transcription factor IIIC. Cell Death Differ. April 2002, 9 (4): 439–47. PMID 11965497. doi:10.1038/sj.cdd.4401038 .
24. Alcivar A, Hu S, Tang J, Yang X. DEDD and DEDD2 associate with caspase-8/10 and signal cell death. Oncogene. January 2003, 22 (2): 291–7. PMID 12527898. doi:10.1038/sj.onc.1206099 .
25. Stegh AH, Schickling O, Ehret A, Scaffidi C, Peterhänsel C, Hofmann TG, Grummt I, Krammer PH, Peter ME. DEDD, a novel death effector domain-containing protein, targeted to the nucleolus. EMBO J. October 1998, 17 (20): 5974–86. PMC 1170924 . PMID 9774341. doi:10.1093/emboj/17.20.5974.
26. Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, Shifrin N, Lee B, Benedict Yen TS, Yen B, Woo T, Malynn BA, Ma A. ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature. February 2009, 457 (7231): 906–9. Bibcode:2009Natur.457..906O. PMC 2642523 . PMID 19060883. doi:10.1038/nature07575.
27. Henshall DC, Araki T, Schindler CK, Shinoda S, Lan JQ, Simon RP. Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures. J. Neurochem. September 2003, 86 (5): 1260–70. PMID 12911633. S2CID 21971958. doi:10.1046/j.1471-4159.2003.01934.x .
28. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. June 1996, 85 (6): 803–15. PMID 8681376. S2CID 7415784. doi:10.1016/s0092-8674(00)81265-9 .
29. Thomas LR, Stillman DJ, Thorburn A. Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen. J. Biol. Chem. September 2002, 277 (37): 34343–8. PMID 12107169. doi:10.1074/jbc.M204169200 .
30. MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J. Biol. Chem. October 1997, 272 (41): 25417–20. PMID 9325248. doi:10.1074/jbc.272.41.25417 .
31. Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, Hackam AS, Tam J, Vaillancourt JP, Houtzager V, Rasper DM, Roy S, Hayden MR, Nicholson DW. Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat. Cell Biol. February 2002, 4 (2): 95–105. PMID 11788820. S2CID 10439592. doi:10.1038/ncb735.
32. Koseki T, Inohara N, Chen S, Núñez G. ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc. Natl. Acad. Sci. U.S.A. April 1998, 95 (9): 5156–60. Bibcode:1998PNAS...95.5156K. PMC 20230 . PMID 9560245. doi:10.1073/pnas.95.9.5156 .
33. Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H. Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis. J. Neurosci. October 1999, 19 (19): 8244–51. PMC 6783010 . PMID 10493725. doi:10.1523/JNEUROSCI.19-19-08244.1999.
34. Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene. August 1999, 18 (31): 4409–15. PMID 10442631. S2CID 20510429. doi:10.1038/sj.onc.1202831.
35. Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L. Activation of the NF-kappaB pathway by caspase 8 and its homologs. Oncogene. September 2000, 19 (39): 4451–60. PMID 11002417. doi:10.1038/sj.onc.1203812 .
36. Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Barker PA. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell. June 2008, 30 (6): 689–700. PMID 18570872. doi:10.1016/j.molcel.2008.05.014 .
37. Leo E, Deveraux QL, Buchholtz C, Welsh K, Matsuzawa S, Stennicke HR, Salvesen GS, Reed JC. TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis. J. Biol. Chem. March 2001, 276 (11): 8087–93. PMID 11098060. doi:10.1074/jbc.M009450200 .

拓展阅读

• Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC. Dynamic Regulation of Neutrophil Survival through Tyrosine Phosphorylation or Dephosphorylation of Caspase-8. Journal of Biological Chemistry. 2008, 283 (9): 5402–5413. PMID 18086677. doi:10.1074/jbc.M706462200 .
• Cohen GM. Caspases: the executioners of apoptosis. Biochem. J. 1997, 326 (Pt 1): 1–16. PMC 1218630 . PMID 9337844. doi:10.1042/bj3260001.
• Siegel RM, Chan FK, Chun HJ, Lenardo MJ. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat. Immunol. 2001, 1 (6): 469–74. PMID 11101867. S2CID 345769. doi:10.1038/82712.
• Ye S, Goldsmith EJ. Serpins and other covalent protease inhibitors. Curr. Opin. Struct. Biol. 2002, 11 (6): 740–5. PMID 11751056. doi:10.1016/S0959-440X(01)00275-5.
• Gupta S. Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules. Exp. Gerontol. 2002, 37 (2–3): 293–9. PMID 11772515. S2CID 30243363. doi:10.1016/S0531-5565(01)00195-4.
• Pomerantz RJ. Effects of HIV-1 Vpr on neuroinvasion and neuropathogenesis. DNA Cell Biol. 2004, 23 (4): 227–38. PMID 15142380. doi:10.1089/104454904773819815.
• Zhao LJ, Zhu H. Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2005, 4 (4): 265–75. PMID 15578977. doi:10.2174/1568008043339668.

外部链接

• 肽酶及其抑制剂的MEROPS在线数据库：C14.009^{[失效链接]}
• Apoptosis & Caspase 8 （页面存档备份，存于互联网档案馆） - 蛋白酶解图谱（英语：The Proteolysis Map）（动画）
• 医学主题词表（MeSH）：Caspase-8
• Caspase-8 （页面存档备份，存于互联网档案馆）
• PDB中UniProt可用的所有结构信息之概述：Q14790 (Caspase-8) 在PDBe-KB（英语：PDBe-KB）。