胱天蛋白酶8

位於2號人類染色體的基因

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。

胱天蛋白酶8
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
別名CASP8;, ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5, caspase 8
外部IDOMIM601763 MGI1261423 HomoloGene7657 GeneCardsCASP8
相關疾病
caspase-8 deficiency[1]
為以下藥物的標靶
emricasan[2]
基因位置(人類
2號染色體
染色體2號染色體[3]
2號染色體
胱天蛋白酶8的基因位置
胱天蛋白酶8的基因位置
基因座2q33.1起始201,233,443 bp[3]
終止201,287,711 bp[3]
RNA表達模式


查閱更多表達數據
直系同源
物種人類小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_001080126
​NM_001277926
​NM_009812

蛋白序列

NP_001073595
​NP_001264855
​NP_033942

基因位置​(UCSC)Chr 2: 201.23 – 201.29 MbChr 1: 58.83 – 58.89 Mb
PubMed​查找[5][6]
維基數據
檢視/編輯人類檢視/編輯小鼠

作用

胱天蛋白酶8是胱天蛋白酶家族的成員。半胱天冬酶的連續激活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。半胱天冬酶的激活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序性細胞死亡。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淋巴結腫大主質器官有時存在淋巴細胞浸潤性疾病,但自身免疫性極小,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。淋巴細胞激活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TB自然殺傷細胞中,通過抗原受體、Fc受體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;而對於激活途徑,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

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