胱天蛋白酶8

胱天蛋白酶8
已知的結構
PDB	直系同源搜尋: PDBe RCSB
PDBID列表
	1F9E、1I4E、1QDU、1QTN、2C2Z、2FUN、2K7Z、2Y1L、3H11、3KJN、3KJQ、4JJ7、4PRZ、4PS1、4ZBW
識別號
別名	CASP8；, ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5, caspase 8
外部ID	OMIM：601763 MGI：1261423 HomoloGene：7657 GeneCards：CASP8
相關疾病
	caspase-8 deficiency
為以下藥物的標靶
	emricasan
基因位置（人類）
染色體	2號染色體
終止	201,287,711 bp
基因位置（小鼠）
染色體	小鼠1號染色體
終止	58,886,662 bp
RNA表達模式
	; ;
	查閱更多表達數據
基因本體
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; • 血漿蛋白結合; • 相同蛋白質結合; • cysteine-type endopeptidase activity involved in apoptotic process; • cysteine-type endopeptidase activity; • 水解酶活性; • 泛素蛋白連接酶結合; • 肽酶活性; • cysteine-type endopeptidase activity involved in execution phase of apoptosis; • death receptor binding; • tumor necrosis factor receptor binding; • 大分子複合物結合;
細胞組分	• cell body; • 細胞質基質; • CD95 death-inducing signaling complex; • ripoptosome; • 核質; • mitochondrial outer membrane; • 死亡誘導信號復合體; • 脂筏模型; • neuron projection; • 細胞骨架; • 細胞質; • 線粒體; • 細胞核; • 大分子複合體;
生物學過程	• regulation of apoptotic process; • response to estradiol; • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; • response to antibiotic; • 腫瘤壞死因子介導的信號通路的調控; • 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; • 含有信號通路的核苷酸結合寡聚結構域; • T細胞活化; • suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process; • 細胞凋亡; • extrinsic apoptotic signaling pathway; • 死亡域受體對外源性凋亡信號通路的負調控; • 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
	841
	12370
	ENSG00000064012
	ENSMUSG00000026029
	Q14790
	O89110
NM_001080124; NM_001080125; NM_001228; NM_033355; NM_033356;
	NM_033357; NM_033358; NM_001372051
	NM_001080126; NM_001277926; NM_009812
NP_001073593; NP_001073594; NP_001219; NP_203519; NP_203520;
	NP_203522; NP_001358980
	NP_001073595; NP_001264855; NP_033942
	維基數據
檢視/編輯人類	檢視/編輯小鼠

胱天蛋白酶8（英語：Caspase 8）是一種胱天蛋白酶，由CASP8基因編碼。該酶很可能作用於胱天蛋白酶3。許多可獲得完整基因組數據的哺乳動物都已鑑定出CASP8直系同源物。^[7]這些獨特的直系同源物也存在於鳥類中。

作用

胱天蛋白酶8是胱天蛋白酶家族的成員。半胱天冬酶的連續活化在細胞凋亡的執行階段發揮着核心作用。半胱天冬酶作為無活性酶原存在，由前結構域、大蛋白酶亞基和小蛋白酶亞基組成。半胱天冬酶的活化需要在保守的天冬氨酸殘基處經歷蛋白水解加工，以產生一大一小兩個亞基組成的異二聚體酶。該蛋白參與Fas和各種細胞凋亡刺激誘導的程式性細胞死亡。該蛋白的N端 FADD樣死亡效應結構域表明它可能與FADD相互作用。這種蛋白質在亨廷頓舞蹈症患者受影響的大腦區域的不溶性部分中檢測到，而在正常對照的大腦區域中未檢測到，這表明它在神經退行性疾病中的作用。已經描述了許多編碼不同亞型的選擇性剪接轉錄物變體，儘管並非所有變體都已確定其全長序列。^[8]

臨床意義

一種非常罕見的免疫系統遺傳性疾病也可能是由該基因的突變引起的。這種疾病稱為CEDS，意思是「胱天蛋白酶8缺乏狀態」。CEDS具有與另一種細胞凋亡遺傳病ALPS 相似的特徵，但前者有免疫缺陷表型。因此，除了復發性鼻竇及肺部感染、復發性皮膚粘膜疱疹病、持續性疣和傳染性軟疣感染以及咖瑪免疫球蛋白過低之外，臨床表現還包括脾腫大和淋巴結腫大。主質器官有時存在淋巴細胞浸潤性疾病，但自體免疫性極小，而且在CEDS患者中尚未觀察到淋巴瘤。CEDS以常染色體隱性方式遺傳。^[9]

CEDS患者的臨床表型呈現出一個悖論，因為胱天蛋白酶8被認為主要是一種促凋亡蛋白酶，主要參與腫瘤壞死因子受體家族死亡受體（例如Fas）的信號轉導。淋巴細胞活化和保護性免疫的缺陷表明胱天蛋白酶8在淋巴細胞中具有額外的信號傳導作用。進一步的研究表明，胱天蛋白酶8在T、B和自然殺傷細胞中，通過抗原受體、Fc受體或 Toll樣受體4刺激後，對轉錄因子「核因子κB」（NF-κB）的誘導至關重要。^[9]

生化方面，發現胱天蛋白酶8進入NF-κB激酶抑制劑（IKK）與上游Bcl10-MALT1（粘膜相關淋巴組織）適配器複合物的複合體中，這對於誘導NF-κB的核轉位至關重要。此外，胱天蛋白酶8的生化形式在這兩種途徑中是不同的。對於死亡途徑，胱天蛋白酶8酶原被切割成亞基，這些亞基組裝形成成熟的、高活性的胱天蛋白酶異四聚體；而對於活化途徑，酶原似乎保持完整，可能是為了限制其蛋白水解功能，但增強其作為適配器蛋白的功能。^[9]

相互作用

胱天蛋白酶8已被證明可以與以下物質相互作用：

附加圖片

TNF-R1信號通路。灰色虛線表示多個步驟

細胞凋亡涉及的信號轉導途徑概述

參見

參考文獻

^ 與胱天蛋白酶8相關的疾病；在維基數據上查看/編輯參考.
^ 對Caspase 8起作用的藥物；在維基數據上查看/編輯參考.
^ ^3.0 ^3.1 ^3.2 GRCh38: Ensembl release 89: ENSG00000064012 - Ensembl, May 2017
^ ^4.0 ^4.1 ^4.2 GRCm38: Ensembl release 89: ENSMUSG00000026029 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ OrthoMaM phylogenetic marker: CASP8 coding sequence. ^{[永久失效連結]}
^ Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase. [2024-02-05]. （原始內容存檔於2009-05-11）.
^ ^9.0 ^9.1 ^9.2 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. （原始內容存檔於2023-03-27）.
^ 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.
^ ^11.0 ^11.1 ^11.2 ^11.3 ^11.4 ^11.5 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  .
^ ^12.0 ^12.1 ^12.2 ^12.3 ^12.4 ^12.5 ^12.6 ^12.7 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  .
^ 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.
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^ 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  .
^ 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  .
^ ^21.0 ^21.1 ^21.2 ^21.3 ^21.4 ^21.5 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  .
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^ 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  .
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^ 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.
^ ^26.0 ^26.1 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.
^ 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  .
^ 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  .
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^ 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  .
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拓展閱讀

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.

外部連結

肽酶及其抑制劑的MEROPS在線數據庫：C14.009^{[失效連結]}
Apoptosis & Caspase 8 （頁面存檔備份，存於互聯網檔案館） - 蛋白酶解圖譜（英語：The Proteolysis Map）（動畫）
醫學主題詞表（MeSH）：Caspase-8
Caspase-8 （頁面存檔備份，存於互聯網檔案館）
PDB中UniProt可用的所有結構資訊之概述：Q14790 (Caspase-8) 在PDBe-KB（英語：PDBe-KB）。

[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.

[refGRCh38Ensembl-3] 3.0 ^3.1 ^3.2 GRCh38: Ensembl release 89: ENSG00000064012 - Ensembl, May 2017

[refGRCm38Ensembl-4] 4.0 ^4.1 ^4.2 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.

[OrthoMaM-7] OrthoMaM phylogenetic marker: CASP8 coding sequence. ^{[永久失效連結]}

[8] Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase. [2024-02-05]. （原始內容存檔於2009-05-11）.

[Chun_2002-9] 9.0 ^9.1 ^9.2 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. （原始內容存檔於2023-03-27）.

[pmid9334338-10] 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.

[pmid15659383-11] 11.0 ^11.1 ^11.2 ^11.3 ^11.4 ^11.5 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  .

[pmid11832478-12] 12.0 ^12.1 ^12.2 ^12.3 ^12.4 ^12.5 ^12.6 ^12.7 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  .

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