胱天蛋白酶1
胱天蛋白酶1/白介素1轉換酶（ICE）是一種進化上保守的酶，可通過蛋白酶解將其他蛋白質（例如炎症細胞因子白血球介素1β和白血球介素18的前體以及細胞焦亡誘導劑Gasdermin D）裂解為活性成熟肽。[5][6][7]作為炎症反應引發劑，它在細胞免疫中發揮着核心作用。一旦通過形成炎性小體複合物而被活化，它會通過裂解啟動促炎反應，從而活化兩種炎性細胞因子：白血球介素1β（IL-1β）和白血球介素18（IL-18）以及細胞焦亡（一種程式性裂解細胞死亡途徑），通過Gasdermin D的裂解。[8]胱天蛋白酶1活化的兩種炎症細胞因子從細胞中排出，進一步誘導鄰近細胞的炎症反應。[9]
細胞表達[編輯]
胱天蛋白酶1在動物界的許多真核生物中在進化上是保守的。由於其在炎症免疫反應中的作用，它在肝、腎、脾和血液（嗜中性顆粒白血球）等免疫器官中高度表達。[10][11]感染後，炎症反應通過正反饋機制增強胱天蛋白酶1的表達，從而放大反應。[11]
結構[編輯]
胱天蛋白酶1作為酶原產生，然後可以裂解成20 kDa（p20）和10 kDa（p10）亞基，成為活性酶的一部分。活性胱天蛋白酶1包含p20和p10兩個異二聚體。它包含一個具有跨越p20和p10亞基的活性位點的催化結構域，[12]以及一個非催化性胱天蛋白酶活化和募集結構域（CARD）。它與其他含有CARD的蛋白質相互作用，例如含有CARD的凋亡相關斑點樣蛋白 (ASC) 和Nod樣受體（NLR）家族含有CARD結構域蛋白4（NLRC4），通過CARD-CARD相互作用形成炎性小體 。[7][13]
調節[編輯]
活化[編輯]
胱天蛋白酶1通常以其生理上無活性的酶原形式存在，當它通過自身蛋白酶解成p10和p20亞基而組裝成絲狀炎性體複合物時，會自動活化。[14][15]炎性小體複合物是一種環狀複合物，由信號特異性傳感器蛋白（例如NLR家族和AIM1樣受體）、銜接蛋白（例如ASC）和胱天蛋白酶（在本例中為胱天蛋白酶1）組成的三聚體。在某些情況下，信號蛋白含有自己的CARD，例如NLRP1和NLRC4，CARD-CARD相互作用是直接的，這意味着複合物中沒有銜接蛋白。有多種傳感器和銜接蛋白，它們的各種組合賦予炎性小體對特定信號的反應。這使得細胞根據收到的危險信號的嚴重程度產生不同程度的炎症反應。[16][17]
抑制[編輯]
僅CARD蛋白（CARD only protein，COP），顧名思義，是僅包含非催化CARD的蛋白質。由於CARD-CARD相互作用在炎性小體形成中的重要性，許多的COP是胱天蛋白酶的已知活化抑制劑。對於胱天蛋白酶1，特定COP的基因——ICEBERG、COP1（ICE/偽ICE）和INCA（抑制卡）——均在其基因座附近發現，因此被認為是由基因複製事件和隨後的催化結構域刪除而產生的。儘管它們都通過CARD-CARD相互作用與炎性小體相互作用，但它們執行抑制功能的方式以及有效性有所不同。[15][18][19]
例如，ICEBERG使胱天蛋白酶1絲的形成成核，並因此摻入絲中，但缺乏抑制炎性小體活化的能力。相反，它被認為通過干擾胱天蛋白酶1與其他重要的含有CARD蛋白的相互作用來抑制胱天蛋白酶1活化。[15][18][19]
另一方面，INCA通過封蓋胱天蛋白酶1 CARD寡聚體來直接阻斷炎性小體組裝，從而阻止進一步聚合成炎性小體絲。[18][19][20][13]
類似地，一些僅Pyrin蛋白（Pyrin only protein，POP）也被認為通過結合併阻斷PYD相互作用來抑制炎性小體活化，從而調節胱天蛋白酶1活化。PYD相互作用也在炎性小體的形成中發揮作用，但具體機制尚不清楚。[19][21]
- 抑制劑
- Belnacasan（VX-765）[22]
- Pralnacasan（VX-740）[23]
功能[編輯]
蛋白酶解裂解[編輯]
活化的胱天蛋白酶1通過蛋白酶解將IL-1β前體和IL-18前體裂解為其活性形式IL-1β和IL-18。活性細胞因子導致下游炎症反應。它還將Gasdermin D裂解為其活性形式，從而導致細胞焦亡。[13]
炎症反應[編輯]
一旦成熟，細胞因子就會啟動下游信號傳導事件，誘導促炎反應並活化抗病毒基因的表達。響應的速度、特異性和類型取決於接收到的信號以及接收到信號的傳感器蛋白。炎性小體可以接收的信號包括病毒雙鏈RNA、尿素、自由基以及與細胞危險相關的其他信號，甚至其他免疫反應途徑的副產物。[24]
成熟的細胞因子本身不含有進入ER-高爾基體分泌途徑所需的分選序列，因此不會通過常規方法從細胞中排出。然而，理論上這些促炎細胞因子的釋放並不依賴於細胞焦亡的細胞破裂，事實上，這是一個活躍的過程。支持和反對這一假設都有證據。對於許多細胞類型來說，儘管它們完全沒有表現出細胞焦亡的跡象，但細胞因子仍然被分泌，這一事實支持了這一假設。[17][25]然而，一些實驗表明，Gasdermin D無功能突變體仍然具有細胞因子的正常裂解，但缺乏分泌細胞因子的能力，這表明細胞焦亡實際上可能以某種方式是分泌所必需的。[26]
焦亡反應[編輯]
炎症反應後，活化的胱天蛋白酶1可以誘導細胞焦亡，這是一種細胞死亡的裂解形式，具體取決於接收到的信號以及接收信號的特定炎性小體傳感器結構域蛋白。儘管完全炎症反應可能需要或不需要焦亡，但在發生焦亡之前完全需要炎症反應。[17]為了誘導細胞焦亡，胱天蛋白酶1將Gasdermin D裂解成在質膜中形成孔的片段。由於滲透壓，這些孔促進液體流入，導致細胞裂解和死亡。[27]
其它功能[編輯]
胱天蛋白酶1還被證明可以誘導壞死，並且還可以在不同的發育階段發揮作用。對小鼠中類似蛋白質的研究表明，它在亨廷頓舞蹈病的發病機制中發揮着作用。基因的選擇性剪接產生編碼不同亞型的五種轉錄變體。[28]最近的研究表明胱天蛋白酶1會促進CD4 T細胞死亡和HIV引起的炎症，這是促進HIV疾病進展為AIDS的兩個標誌性事件。[29][30][31] 胱天蛋白酶1活性還與細菌[32]和免疫複合物吞噬後的溶酶體酸化有關。[33]
參見[編輯]
參考資料[編輯]
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外部連結[編輯]
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![1bmq: CRYSTAL STRUCTURE OF THE COMPLEX OF INTERLEUKIN-1BETA CONVERTING ENZYME (ICE) WITH A PEPTIDE BASED INHIBITOR, (3S )-N-METHANESULFONYL-3-({1-[N-(2-NAPHTOYL)-L-VALYL]-L-PROLYL }AMINO)-4-OXOBUTANAMIDE](/wiki/File:PDB_1bmq_EBI.jpg)
![1rwm: Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5[4-(quinoxalin-2-ylamino)-benzoylamino]-methylthiophen-2-yl)-acetylamino]-pentanoic acid](/wiki/File:PDB_1rwm_EBI.jpg)
![1rwn: Crystal structure of human caspase-1 in complex with 32-ethyl-6-[4-(quinoxalin-2-ylamino)-benzoylamino]-hexanoylamino4-oxo-butyric acid](/wiki/File:PDB_1rwn_EBI.jpg)
![1rwo: Crystal structure of human caspase-1 in complex with 4-oxo-36-[4-(quinoxalin-2-ylamino)-benzoylamino]-2-thiophen-2-yl-hexanoylaminopentanoic acid](/wiki/File:PDB_1rwo_EBI.jpg)
![1rwp: Crystal structure of human caspase-1 in complex with 36-[(8-hydroxy-quinoline-2-carbonyl)-amino]-2-thiophen-2-yl-hexanoylamino4-oxo-butyric acid](/wiki/File:PDB_1rwp_EBI.jpg)
![1rwv: Crystal structure of human caspase-1 in complex with 5-[5-(1-carboxymethyl-2-oxo-propylcarbamoyl)-5-phenyl-pentylsulfamoyl]-2-hydroxy-benzoic acid](/wiki/File:PDB_1rwv_EBI.jpg)
![1rww: Crystal structure of human caspase-1 in complex with 4-oxo-3-[(6[4-(quinoxalin-2-ylamino)-benzoylamino]-methylpyridine-3-carbonyl)-amino]-butyric acid](/wiki/File:PDB_1rww_EBI.jpg)
![1rwx: Crystal structure of human caspase-1 in complex with 4-oxo-36-[4-(quinoxalin-2-yloxy)-benzoylamino]-2-thiophen-2-yl-hexanoylaminobutyric acid](/wiki/File:PDB_1rwx_EBI.jpg)
![2fqq: Crystal structure of human caspase-1 (Cys285->Ala, Cys362->Ala, Cys364->Ala, Cys397->Ala) in complex with 1-methyl-3-trifluoromethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (2-mercapto-ethyl)-amide](/wiki/File:PDB_2fqq_EBI.png)
![2h48: Crystal structure of human caspase-1 (Cys362->Ala, Cys364->Ala, Cys397->Ala) in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)](/wiki/File:PDB_2h48_EBI.png)
![2hbq: Crystal structure of wildtype human caspase-1 in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)](/wiki/File:PDB_2hbq_EBI.png)
![2hbr: Crystal structure of human caspase-1 (Arg286->Ala) in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)](/wiki/File:PDB_2hbr_EBI.png)
![2hby: Crystal structure of human caspase-1 (Glu390->Ala) in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)](/wiki/File:PDB_2hby_EBI.png)
![2hbz: Crystal structure of human caspase-1 (Arg286->Ala, Glu390->Ala) in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)](/wiki/File:PDB_2hbz_EBI.png)
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