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Yersinia pestis Ail recruitment of C4b-binding protein leads to factor I- mediated inactivation of covalently and noncovalently bound C4b

Ho, Derek K.; Skurnik, Mikael; Blom, Anna LU and Meri, Seppo (2014) In European Journal of Immunology 44(3). p.742-751
Abstract
The outer membrane protein Ail of Yersinia pestis mediates several virulence functions, including serum resistance. Here, we demonstrate that Ail binds C4b-binding protein (C4BP), the primary fluid-phase regulator of the classical and lectin pathways. Non-covalent binding of C4 and C4b to Ail was also observed. C4BP bound to Ail can act as a cofactor to the serine protease factor I (fI) in the cleavage of fluid-phase C4b. Employing a panel of C4BP alpha-chain mutants, we observed that the absence of complement control protein domain 6 and 8 reduced binding to Ail. Immunoblot analysis of normal human serum (NHS)-treated bacteria revealed minimal C4b alpha'-chain complexes with bacterial outer membrane targets. Addition of the anti-C4BP... (More)
The outer membrane protein Ail of Yersinia pestis mediates several virulence functions, including serum resistance. Here, we demonstrate that Ail binds C4b-binding protein (C4BP), the primary fluid-phase regulator of the classical and lectin pathways. Non-covalent binding of C4 and C4b to Ail was also observed. C4BP bound to Ail can act as a cofactor to the serine protease factor I (fI) in the cleavage of fluid-phase C4b. Employing a panel of C4BP alpha-chain mutants, we observed that the absence of complement control protein domain 6 and 8 reduced binding to Ail. Immunoblot analysis of normal human serum (NHS)-treated bacteria revealed minimal C4b alpha'-chain complexes with bacterial outer membrane targets. Addition of the anti-C4BP monoclonal antibody MK104 to NHS restored C4b-alpha' chain target complexes, suggesting that C4b binds covalently to targets on the Y. pestis surface. C4b bound to Ail noncovalently was also cleaved in a C4BP and fI-dependent manner, leaving the C4c fragment bound to Ail. MK104 also prevented the cleavage of noncovalently bound C4b. Collectively, these data suggest that when C4BP is bound to Ail, fI can cleave and inactivate C4b that has bound covalently to bacterial surface structures as well as C4b bound noncovalently to Ail. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ail, C4b-binding protein, Complement, Yersinia
in
European Journal of Immunology
volume
44
issue
3
pages
742 - 751
publisher
John Wiley & Sons
external identifiers
  • wos:000332933200016
  • scopus:84896050071
ISSN
1521-4141
DOI
10.1002/eji.201343552
language
English
LU publication?
yes
id
9d26f66f-595b-4a28-afda-889b4a7e383b (old id 4439912)
date added to LUP
2014-07-01 07:45:04
date last changed
2017-10-22 03:10:50
@article{9d26f66f-595b-4a28-afda-889b4a7e383b,
  abstract     = {The outer membrane protein Ail of Yersinia pestis mediates several virulence functions, including serum resistance. Here, we demonstrate that Ail binds C4b-binding protein (C4BP), the primary fluid-phase regulator of the classical and lectin pathways. Non-covalent binding of C4 and C4b to Ail was also observed. C4BP bound to Ail can act as a cofactor to the serine protease factor I (fI) in the cleavage of fluid-phase C4b. Employing a panel of C4BP alpha-chain mutants, we observed that the absence of complement control protein domain 6 and 8 reduced binding to Ail. Immunoblot analysis of normal human serum (NHS)-treated bacteria revealed minimal C4b alpha'-chain complexes with bacterial outer membrane targets. Addition of the anti-C4BP monoclonal antibody MK104 to NHS restored C4b-alpha' chain target complexes, suggesting that C4b binds covalently to targets on the Y. pestis surface. C4b bound to Ail noncovalently was also cleaved in a C4BP and fI-dependent manner, leaving the C4c fragment bound to Ail. MK104 also prevented the cleavage of noncovalently bound C4b. Collectively, these data suggest that when C4BP is bound to Ail, fI can cleave and inactivate C4b that has bound covalently to bacterial surface structures as well as C4b bound noncovalently to Ail.},
  author       = {Ho, Derek K. and Skurnik, Mikael and Blom, Anna and Meri, Seppo},
  issn         = {1521-4141},
  keyword      = {Ail,C4b-binding protein,Complement,Yersinia},
  language     = {eng},
  number       = {3},
  pages        = {742--751},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Yersinia pestis Ail recruitment of C4b-binding protein leads to factor I- mediated inactivation of covalently and noncovalently bound C4b},
  url          = {http://dx.doi.org/10.1002/eji.201343552},
  volume       = {44},
  year         = {2014},
}