埃博拉病毒糖蛋白的内体蛋白水解作用对于感染是必要的。
Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection.
作者信息
Chandran Kartik, Sullivan Nancy J, Felbor Ute, Whelan Sean P, Cunningham James M
机构信息
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
出版信息
Science. 2005 Jun 10;308(5728):1643-5. doi: 10.1126/science.1110656. Epub 2005 Apr 14.
Abstract
Ebola virus (EboV) causes rapidly fatal hemorrhagic fever in humans and there is currently no effective treatment. We found that the infection of African green monkey kidney (Vero) cells by vesicular stomatitis viruses bearing the EboV glycoprotein (GP) requires the activity of endosomal cysteine proteases. Using selective protease inhibitors and protease-deficient cell lines, we identified an essential role for cathepsin B (CatB) and an accessory role for cathepsin L (CatL) in EboV GP-dependent entry. Biochemical studies demonstrate that CatB and CatL mediate entry by carrying out proteolysis of the EboV GP subunit GP1 and support a multistep mechanism that explains the relative contributions of these enzymes to infection. CatB and CatB/CatL inhibitors diminish the multiplication of infectious EboV-Zaire in cultured cells and may merit investigation as anti-EboV drugs.
摘要
埃博拉病毒（EboV）可导致人类迅速患上致命的出血热，目前尚无有效治疗方法。我们发现，携带埃博拉病毒糖蛋白（GP）的水疱性口炎病毒感染非洲绿猴肾（Vero）细胞需要内体半胱氨酸蛋白酶的活性。通过使用选择性蛋白酶抑制剂和蛋白酶缺陷细胞系，我们确定了组织蛋白酶B（CatB）在依赖埃博拉病毒GP的进入过程中的关键作用以及组织蛋白酶L（CatL）的辅助作用。生化研究表明，CatB和CatL通过对埃博拉病毒GP亚基GP1进行蛋白水解来介导进入，并支持一种多步骤机制，该机制解释了这些酶对感染的相对贡献。CatB和CatB/CatL抑制剂可减少感染性埃博拉病毒扎伊尔型在培养细胞中的增殖，可能值得作为抗埃博拉病毒药物进行研究。
相似文献
1
Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection.埃博拉病毒糖蛋白的内体蛋白水解作用对于感染是必要的。
Science. 2005 Jun 10;308(5728):1643-5. doi: 10.1126/science.1110656. Epub 2005 Apr 14.
2
Novel proteolytic activation of Ebolavirus glycoprotein GP by TMPRSS2 and cathepsin L at an uncharted position can compensate for furin cleavage.新型蛋白酶 TMPRSS2 和组织蛋白酶 L 在一个未知位置对埃博拉病毒糖蛋白 GP 的蛋白水解激活作用可以弥补弗林蛋白酶的切割作用。
Virus Res. 2024 Sep;347:199430. doi: 10.1016/j.virusres.2024.199430. Epub 2024 Jul 8.
3
Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein.内体组织蛋白酶在埃博拉病毒糖蛋白介导的病毒进入过程中的作用
J Virol. 2006 Apr;80(8):4174-8. doi: 10.1128/JVI.80.8.4174-4178.2006.
4
Cathepsin B & L are not required for ebola virus replication.组织蛋白酶 B 和 L 对于埃博拉病毒的复制不是必需的。
PLoS Negl Trop Dis. 2012;6(12):e1923. doi: 10.1371/journal.pntd.0001923. Epub 2012 Dec 6.
5
Inhibitors of signal peptide peptidase and subtilisin/kexin-isozyme 1 inhibit Ebola virus glycoprotein-driven cell entry by interfering with activity and cellular localization of endosomal cathepsins.信号肽肽酶和枯草杆菌蛋白酶/kexin 同工酶 1 的抑制剂通过干扰内体组织蛋白酶的活性和细胞定位来抑制埃博拉病毒糖蛋白驱动的细胞进入。
PLoS One. 2019 Apr 11;14(4):e0214968. doi: 10.1371/journal.pone.0214968. eCollection 2019.
6
Proteolysis of the Ebola virus glycoproteins enhances virus binding and infectivity.埃博拉病毒糖蛋白的蛋白水解作用增强病毒结合及感染性。
J Virol. 2007 Dec;81(24):13378-84. doi: 10.1128/JVI.01170-07. Epub 2007 Oct 10.
7
How Ebola virus infects cells.埃博拉病毒如何感染细胞。
N Engl J Med. 2005 Jun 23;352(25):2645-6. doi: 10.1056/NEJMcibr051754.
8
A forward genetic strategy reveals destabilizing mutations in the Ebolavirus glycoprotein that alter its protease dependence during cell entry.一种正向遗传策略揭示了埃博拉病毒糖蛋白中的不稳定突变，这些突变改变了其在细胞进入过程中对蛋白酶的依赖性。
J Virol. 2010 Jan;84(1):163-75. doi: 10.1128/JVI.01832-09.
9
Zaire Ebola virus entry into human dendritic cells is insensitive to cathepsin L inhibition.扎伊尔埃博拉病毒进入人树突状细胞对组织蛋白酶 L 抑制不敏感。
Cell Microbiol. 2010 Feb;12(2):148-57. doi: 10.1111/j.1462-5822.2009.01385.x. Epub 2009 Sep 22.
10
Growth-Adaptive Mutations in the Ebola Virus Makona Glycoprotein Alter Different Steps in the Virus Entry Pathway.埃博拉病毒马科纳糖蛋白中的生长适应性突变改变了病毒进入途径的不同步骤。
J Virol. 2018 Sep 12;92(19). doi: 10.1128/JVI.00820-18. Print 2018 Oct 1.
引用本文的文献
1
Small molecule drug discovery for Ebola virus disease.针对埃博拉病毒病的小分子药物研发
RSC Med Chem. 2025 Aug 6. doi: 10.1039/d5md00533g.
2
agglutinin enhances entry through interactions at specific -linked glycosylation sites on the virus glycoprotein complex.凝集素通过与病毒糖蛋白复合物上特定连接的糖基化位点相互作用来增强病毒进入。
J Gen Virol. 2025 Jun;106(6). doi: 10.1099/jgv.0.002120.
3
From Diarylsulfides to Diarylamines: New Ebola Virus Entry Inhibitors with Improved Metabolic Stability.从二芳基硫醚到二芳基胺：具有改善代谢稳定性的新型埃博拉病毒进入抑制剂。
J Med Chem. 2025 Jun 12;68(11):11786-11800. doi: 10.1021/acs.jmedchem.5c00615. Epub 2025 May 17.
4
Marburg Virus Disease: A Narrative Review.马尔堡病毒病：一篇叙述性综述。
Health Sci Rep. 2025 May 6;8(5):e70669. doi: 10.1002/hsr2.70669. eCollection 2025 May.
5
Molecular basis for the increased fusion activity of the Ebola virus glycoprotein epidemic variant A82V: Insights from simulations and experiments.埃博拉病毒糖蛋白流行变体A82V融合活性增强的分子基础：来自模拟和实验的见解
Cell Rep. 2025 Apr 22;44(4):115521. doi: 10.1016/j.celrep.2025.115521. Epub 2025 Apr 4.
6
Cathepsins in cellular entry of human pathogenic viruses.组织蛋白酶在人类致病病毒的细胞进入过程中的作用
J Virol. 2025 Apr 15;99(4):e0164224. doi: 10.1128/jvi.01642-24. Epub 2025 Mar 26.
7
Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP in a position elevated from the virion membrane.抗埃博拉病毒单克隆抗体3A6通过结合位于病毒体膜上方位置的糖蛋白（GP），保护高病毒血症动物免于致命后果。
Nat Commun. 2025 Feb 3;16(1):1293. doi: 10.1038/s41467-025-56452-2.
8
Cryo-EM structure of Sudan ebolavirus glycoprotein complexed with its human endosomal receptor NPC1.与人类内体受体NPC1复合的苏丹埃博拉病毒糖蛋白的冷冻电镜结构
Commun Biol. 2025 Feb 2;8(1):156. doi: 10.1038/s42003-025-07613-y.
9
Bat genomes illuminate adaptations to viral tolerance and disease resistance.蝙蝠基因组揭示了对病毒耐受性和疾病抗性的适应性。
Nature. 2025 Feb;638(8050):449-458. doi: 10.1038/s41586-024-08471-0. Epub 2025 Jan 29.
10
Identification of Filovirus Entry Inhibitors from Marine Fungus-Derived Indole Alkaloids.从海洋真菌衍生的吲哚生物碱中鉴定丝状病毒进入抑制剂。
Mar Drugs. 2025 Jan 3;23(1):23. doi: 10.3390/md23010023.
本文引用的文献
1
The many mechanisms of viral membrane fusion proteins.病毒膜融合蛋白的多种机制。
Curr Top Microbiol Immunol. 2005;285:25-66. doi: 10.1007/3-540-26764-6_2.
2
Exotic emerging viral diseases: progress and challenges.外来新发病毒性疾病：进展与挑战
Nat Med. 2004 Dec;10(12 Suppl):S110-21. doi: 10.1038/nm1142.
3
Folate receptor alpha and caveolae are not required for Ebola virus glycoprotein-mediated viral infection.埃博拉病毒糖蛋白介导的病毒感染不需要叶酸受体α和小窝。
J Virol. 2003 Dec;77(24):13433-8. doi: 10.1128/jvi.77.24.13433-13438.2003.
4
Animal cell invasion by a large nonenveloped virus: reovirus delivers the goods.大型无包膜病毒对动物细胞的侵袭：呼肠孤病毒传递物质。
Trends Microbiol. 2003 Aug;11(8):374-82. doi: 10.1016/s0966-842x(03)00178-1.
5
DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells.树突状细胞特异性细胞间黏附分子-3抓取非整合素（DC-SIGN）和树突状细胞特异性细胞间黏附分子-3抓取非整合素相关分子（DC-SIGNR）可结合埃博拉病毒糖蛋白并增强巨噬细胞和内皮细胞的感染。
Virology. 2003 Jan 5;305(1):115-23. doi: 10.1006/viro.2002.1730.
6
Covalent modifications of the ebola virus glycoprotein.埃博拉病毒糖蛋白的共价修饰
J Virol. 2002 Dec;76(24):12463-72. doi: 10.1128/jvi.76.24.12463-12472.2002.
7
Neuronal loss and brain atrophy in mice lacking cathepsins B and L.缺乏组织蛋白酶B和L的小鼠的神经元丢失和脑萎缩
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7883-8. doi: 10.1073/pnas.112632299. Epub 2002 Jun 4.
8
Cathepsin L and cathepsin B mediate reovirus disassembly in murine fibroblast cells.组织蛋白酶L和组织蛋白酶B介导呼肠孤病毒在小鼠成纤维细胞中的解体。
J Biol Chem. 2002 Jul 5;277(27):24609-17. doi: 10.1074/jbc.M201107200. Epub 2002 May 1.
9
Cysteine Proteases and Their Inhibitors.半胱氨酸蛋白酶及其抑制剂
Chem Rev. 1997 Feb 5;97(1):133-172. doi: 10.1021/cr950025u.
10
Retroviral entry mediated by receptor priming and low pH triggering of an envelope glycoprotein.由受体引发和包膜糖蛋白的低pH触发介导的逆转录病毒进入。
Cell. 2000 Nov 10;103(4):679-89. doi: 10.1016/s0092-8674(00)00170-7.
Zotero 插件