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Binding of Flavivirus Nonstructural Protein NS1 to C4b Binding Protein Modulates Complement Activation

Avirutnan, Panisadee; Hauhart, Richard E.; Somnuke, Pawit; Blom, Anna LU ; Diamond, Michael S. and Atkinson, John P. (2011) In Journal of Immunology 187(1). p.424-433
Abstract
The complement system plays a pivotal protective role in the innate immune response to many pathogens including flaviviruses. Flavivirus nonstructural protein 1 (NS1) is a secreted nonstructural glycoprotein that accumulates in plasma to high levels and is displayed on the surface of infected cells but absent from viral particles. Previous work has defined an immune evasion role of flavivirus NS1 in limiting complement activation by forming a complex with C1s and C4 to promote cleavage of C4 to C4b. In this study, we demonstrate a second mechanism, also involving C4 and its active fragment C4b, by which NS1 antagonizes complement activation. Dengue, West Nile, or yellow fever virus NS1 directly associated with C4b binding protein (C4BP), a... (More)
The complement system plays a pivotal protective role in the innate immune response to many pathogens including flaviviruses. Flavivirus nonstructural protein 1 (NS1) is a secreted nonstructural glycoprotein that accumulates in plasma to high levels and is displayed on the surface of infected cells but absent from viral particles. Previous work has defined an immune evasion role of flavivirus NS1 in limiting complement activation by forming a complex with C1s and C4 to promote cleavage of C4 to C4b. In this study, we demonstrate a second mechanism, also involving C4 and its active fragment C4b, by which NS1 antagonizes complement activation. Dengue, West Nile, or yellow fever virus NS1 directly associated with C4b binding protein (C4BP), a complement regulatory plasma protein that attenuates the classical and lectin pathways. Soluble NS1 recruited C4BP to inactivate C4b in solution and on the plasma membrane. Mapping studies revealed that the interaction sites of NS1 on C4BP partially overlap with the C4b binding sites. Together, these studies further define the immune evasion potential of NS1 in reducing the functional capacity of C4 in complement activation and control of flavivirus infection. The Journal of Immunology, 2011, 187: 424-433. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
187
issue
1
pages
424 - 433
publisher
American Association of Immunologists
external identifiers
  • wos:000291799300049
  • scopus:79960404180
ISSN
1550-6606
DOI
10.4049/jimmunol.1100750
language
English
LU publication?
yes
id
29ea1cd0-4793-4189-9562-685843441830 (old id 2052560)
date added to LUP
2011-08-02 09:01:14
date last changed
2017-11-19 03:58:23
@article{29ea1cd0-4793-4189-9562-685843441830,
  abstract     = {The complement system plays a pivotal protective role in the innate immune response to many pathogens including flaviviruses. Flavivirus nonstructural protein 1 (NS1) is a secreted nonstructural glycoprotein that accumulates in plasma to high levels and is displayed on the surface of infected cells but absent from viral particles. Previous work has defined an immune evasion role of flavivirus NS1 in limiting complement activation by forming a complex with C1s and C4 to promote cleavage of C4 to C4b. In this study, we demonstrate a second mechanism, also involving C4 and its active fragment C4b, by which NS1 antagonizes complement activation. Dengue, West Nile, or yellow fever virus NS1 directly associated with C4b binding protein (C4BP), a complement regulatory plasma protein that attenuates the classical and lectin pathways. Soluble NS1 recruited C4BP to inactivate C4b in solution and on the plasma membrane. Mapping studies revealed that the interaction sites of NS1 on C4BP partially overlap with the C4b binding sites. Together, these studies further define the immune evasion potential of NS1 in reducing the functional capacity of C4 in complement activation and control of flavivirus infection. The Journal of Immunology, 2011, 187: 424-433.},
  author       = {Avirutnan, Panisadee and Hauhart, Richard E. and Somnuke, Pawit and Blom, Anna and Diamond, Michael S. and Atkinson, John P.},
  issn         = {1550-6606},
  language     = {eng},
  number       = {1},
  pages        = {424--433},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Binding of Flavivirus Nonstructural Protein NS1 to C4b Binding Protein Modulates Complement Activation},
  url          = {http://dx.doi.org/10.4049/jimmunol.1100750},
  volume       = {187},
  year         = {2011},
}