Document Detail


Activation of the alphavirus spike protein is suppressed by bound E3.
MedLine Citation:
PMID:  21430054     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Alphaviruses are taken up into the endosome of the cell, where acidic conditions activate the spikes for membrane fusion. This involves dissociation of the three E2-E1 heterodimers of the spike and E1 interaction with the target membrane as a homotrimer. The biosynthesis of the heterodimer as a pH-resistant p62-E1 precursor appeared to solve the problem of premature activation in the late and acidic parts of the biosynthetic transport pathway in the cell. However, p62 cleavage into E2 and E3 by furin occurs before the spike has left the acidic compartments, accentuating the problem. In this work, we used a furin-resistant Semliki Forest virus (SFV) mutant, SFV(SQL), to study the role of E3 in spike activation. The cleavage was reconstituted with proteinase K in vitro using free virus or spikes on SFV(SQL)-infected cells. We found that E3 association with the spikes was pH dependent, requiring acidic conditions, and that the bound E3 suppressed spike activation. This was shown in an in vitro spike activation assay monitoring E1 trimer formation with liposomes and a fusion-from-within assay with infected cells. Furthermore, the wild type, SFV(wt), was found to bind significant amounts of E3, especially if produced in dense cultures, which lowered the pH of the culture medium. This E3 also suppressed spike activation. The results suggest that furin-cleaved E3 continues to protect the spike from premature activation in acidic compartments of the cell and that its release in the neutral extracellular space primes the spike for low-pH activation.
Authors:
Mathilda Sjöberg; Birgitta Lindqvist; Henrik Garoff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-23
Journal Detail:
Title:  Journal of virology     Volume:  85     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-09     Completed Date:  2011-07-13     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5644-50     Citation Subset:  IM    
Affiliation:
Department of Biosciences and Nutrition, Karolinska Institute, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cricetinae
Endopeptidase K / metabolism
Furin / metabolism
Membrane Glycoproteins / metabolism*
Protein Binding
Semliki forest virus / physiology*
Viral Envelope Proteins / metabolism*
Chemical
Reg. No./Substance:
0/Membrane Glycoproteins; 0/Viral Envelope Proteins; EC 3.4.21.64/Endopeptidase K; EC 3.4.21.75/Furin
Comments/Corrections

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