Staphylococcus aureus Protein A Activates TNFR1 Signaling through Conserved IgG Binding Domains
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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, protein A (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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SpA binds TNF receptor 1 (TNFR1) and EGF receptor (EGFR).
“SpA has numerous interactions with host immune effectors binding TNF receptor 1 (TNFR1) (13), EGF receptor (EGFR) (14), IgG (15), and von Willebrand factor (16) as well as activating B cell clonal expansion (17).”
From Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity (2011) · cites this paper as [13]
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- Authors
- Gómez, M. I., O'Seaghdha, M., Magargee, M., Foster, T. J., & Prince, A. S.
- Affiliations
- Columbia University (US)
- Columbia University Irving Medical Center (US)
- Trinity College Dublin (IE)
- Corresponding author
- Prince, Alice S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 281
- Issue
- 29
- Pages
- 20190-20196
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2003071799
- Cited by
- 155
- References
- 37
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 13 · 2015: 12 · 2014: 10 · 2013: 16 · 2012: 14
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Health Research Board
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL079395)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- Staphylococcus aureus, protein A, IgG-binding domain, TNFR1 signaling, interleukin-8, chemokine induction, opsonization, methicillin-resistant Staphylococcus aureus, airway epithelial cells, inflammation, bacterial virulence factors
- MeSH terms
- Amino Acid Sequence, Base Sequence, Binding Sites, Cloning, Molecular, Escherichia coli, Immunoglobulin G, Models, Molecular, Molecular Sequence Data, Protein Conformation, Recombinant Fusion Proteins, Recombinant Proteins, Staphylococcal Protein A, Mutagenesis, Site-Directed, Protein Structure, Secondary, Respiratory Mucosa, Receptors, Tumor Necrosis Factor, Type I
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