Staphylococcus aureus protein A activates TNFR1 signaling through conserved IgG binding domains

被引:109
作者
Gomez, Marisa I.
O'Seaghdha, Maghnus
Magargee, Mariah
Foster, Timothy J.
Prince, Alice S.
机构
[1] Columbia Univ, Coll Phys & Surg, Dept Pediat, New York, NY 10032 USA
[2] Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
[3] Univ Dublin Trinity Coll, Moyne Inst Prevent Med, Dept Microbiol, Dublin 2, Ireland
关键词
D O I
10.1074/jbc.M601956200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Staphylococcus aureus continues to be a major cause of infection in normal as well as immunocompromised hosts, and the increasing prevalence of highly virulent community-acquired methicillin-resistant strains is a public health concern. A highly expressed surface component of S. aureus, proteinA(SpA), contributes to its success as a pathogen by both activating inflammation and by interfering with immune clearance. SpA is known to bind to IgG Fc, which impedes phagocytosis. SpA is also a potent activator of tumor necrosis factor alpha(TNF-alpha) receptor 1 (TNFR1) signaling, inducing both chemokine expression and TNF-converting enzyme-dependent soluble TNFR1 (sTNFR1) shedding, which has anti-inflammatory consequences, particularly in the lung. Using a collection of glutathione S-transferase fusions to the intact IgG binding region of SpA and to each of the individual binding domains, we found that the SpA IgG binding domains also mediate binding to human airway cells. TNFR1-dependent CXCL8 production could be elicited by any one of the individual SpA IgG binding domains as efficiently as by either the entire SpA or the intact IgG binding region. SpA induction of sTNFR1 shedding required the entire IgG binding region and tolerated fewer substitutions in residues known to interact with IgG. Each of the repeated domains of the IgG binding domain can affect multiple immune responses independently, activating inflammation through TNFR1 and thwarting opsonization by trapping IgG Fc domains, while the intact IgG binding region can limit further signaling through sTNFR1 shedding.
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收藏
页码:20190 / 20196
页数:7
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