دورية أكاديمية
A Glycoprotein Mutation That Emerged during the 2013-2016 Ebola Virus Epidemic Alters Proteolysis and Accelerates Membrane Fusion.
| العنوان: | A Glycoprotein Mutation That Emerged during the 2013-2016 Ebola Virus Epidemic Alters Proteolysis and Accelerates Membrane Fusion. |
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| المؤلفون: | Fels JM; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Bortz RH 3rd; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Alkutkar T; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Mittler E; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Jangra RK; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA., Spence JS; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA jspence008@gmail.com kartik.chandran@einsteinmed.org., Chandran K; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA jspence008@gmail.com kartik.chandran@einsteinmed.org. |
| المصدر: | MBio [mBio] 2021 Feb 16; Vol. 12 (1). Date of Electronic Publication: 2021 Feb 16. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Epidemics* , Mutation* , Proteolysis* , Virus Internalization*, Ebolavirus/*genetics , Membrane Fusion/*genetics , Viral Envelope Proteins/*genetics, Africa, Western ; Amino Acid Substitution/genetics ; Animals ; Cathepsin L/metabolism ; Cell Line ; Chlorocebus aethiops ; Hemorrhagic Fever, Ebola/virology ; Humans ; Vero Cells |
| مستخلص: | Genomic surveillance of viral isolates during the 2013-2016 Ebola virus epidemic in Western Africa, the largest and most devastating filovirus outbreak on record, revealed several novel mutations. The responsible strain, named Makona, carries an A-to-V substitution at position 82 (A82V) in the glycoprotein (GP), which is associated with enhanced infectivity in vitro Here, we investigated the mechanistic basis for this enhancement as well as the interplay between A82V and a T-to-I substitution at residue 544 of GP, which also modulates infectivity in cell culture. We found that both 82V and 544I destabilize GP, with the residue at position 544 impacting overall stability, while 82V specifically destabilizes proteolytically cleaved GP. Both residues also promote faster kinetics of lipid mixing of the viral and host membranes in live cells, individually and in tandem, which correlates with faster times to fusion following colocalization with the viral receptor Niemann-Pick C1 (NPC1). Furthermore, GPs bearing 82V are more sensitive to proteolysis by cathepsin L (CatL), a key host factor for viral entry. Intriguingly, CatL processed 82V variant GPs to a novel product with a molecular weight of approximately 12,000 (12K), which we hypothesize corresponds to a form of GP that is pre-triggered for fusion. We thus propose a model in which 82V promotes more efficient GP processing by CatL, leading to faster viral fusion kinetics and higher levels of infectivity. IMPORTANCE The 2013-2016 outbreak of Ebola virus disease in West Africa demonstrated the potential for previously localized outbreaks to turn into regional, or even global, health emergencies. With over 28,000 cases and 11,000 confirmed deaths, this outbreak was over 50 times as large as any previously recorded. This outbreak also afforded the largest-ever collection of Ebola virus genomic sequence data, allowing new insights into viral transmission and evolution. Viral mutants arising during the outbreak have attracted attention for their potentially altered patterns of infectivity in cell culture, with potential, if unclear, implications for increased viral spread and/or virulence. Here, we report the properties of one such mutation in the viral glycoprotein, A82V, and its interplay with a previously described polymorphism at position 544. We show that mutations at both residues promote infection and fusion activation in cells but that A82V additionally leads to increased infectivity under cathepsin-limited conditions and the generation of a novel glycoprotein cleavage product. (Copyright © 2021 Fels et al.) |
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| معلومات مُعتمدة: | R01 AI134824 United States AI NIAID NIH HHS; T32 GM007288 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: Ebola virus; proteolysis; variant surface glycoprotein |
| المشرفين على المادة: | 0 (Viral Envelope Proteins) EC 3.4.22.15 (Cathepsin L) |
| تواريخ الأحداث: | Date Created: 20210217 Date Completed: 20210909 Latest Revision: 20211109 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC8545129 |
| DOI: | 10.1128/mBio.03616-20 |
| PMID: | 33593971 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mBio.03616-20 |