Staphylococcal Superantigen-like 10 Inhibits CXCL12-Induced Human Tumor Cell Migration

Walenkamp, Annemiek; Boer, Ingrid G. J.; Bestebroer, Jovanka; Rozeveld, Dennie; Timmer‐Bosscha, Hetty; Hemrika, Wieger; Strijp, Jos A. G. van; Haas, Carla J. C. de

doi:10.1593/neo.81508

Cited by 68 publications

(47 citation statements)

References 48 publications

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“…SSL7 binds to IgA and C5 (21); SSL5 binds to PSGL-1 (4), chemoattractant receptors (5), and MMP-9 (15), and SSL10 binds to chemokine receptor (32) and human IgG (16,23). Therefore, the SSL family is able to interfere with multiple points of host immunity, especially humoral immunity, opsonization, and trafficking of leukocytes.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that SSL5 binds to matrix metalloproteinase 9 (MMP-9), a member of the zinc-dependent endopeptidase family that is responsible for the degradation of extracellular matrix, and inhibits its proteolytic activity and transmigration of neutrophils through Matrigel basement membrane (15). SSL10 binds to chemokine receptors and inhibits chemotaxis of tumor cells (32). SSL10 also binds to human IgG and inhibits the interaction of IgG with complement C1q and the Fc␥ receptor (16,23).…”

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confidence: 99%

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Staphylococcal Superantigen-Like Protein 3 Binds to the Toll-Like Receptor 2 Extracellular Domain and Inhibits Cytokine Production Induced by Staphylococcus aureus, Cell Wall Component, or Lipopeptides in Murine Macrophages

et al. 2012

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c Staphylococcal superantigen-like proteins (SSLs) are a family of exoproteins sharing structural similarity with superantigens, but no superantigenic activity. Corresponding host target proteins or receptors against a portion of SSLs in the family have been identified. In this study, we show that SSL3 specifically binds to Toll-like receptor 2 (TLR2) and inhibits the stimulation of macrophages by TLR2 ligands. An approximately 100-kDa protein was recovered by using recombinant His-tagged SSL3-conjugated Sepharose from the lysate of porcine spleen, and the protein was identified as porcine TLR2 by peptide mass fingerprinting analysis. The SSL3-conjugated Sepharose recovered human and mouse TLR2 but not TLR4 from human neutrophils and mouse macrophage RAW 264.7 cells, as well as a recombinant TLR2 extracellular domain chimera protein. The production levels of interleukin 12 (IL-12) from mouse macrophages treated with heat-killed Staphylococcus aureus and of tumor necrosis factor alpha (TNF-␣) from RAW 264.7 cells induced by peptidoglycan or lipopeptide TLR2 ligands were strongly suppressed in the presence of SSL3. The mutation of consensus sialic acid-containing glycan-binding residues in SSL3 did not abrogate the binding ability to TLR2 or inhibitory activity on TLR2, indicating that the interaction of SSL3 with TLR2 was independent of the sialic acid-containing glycan-binding residues. These findings demonstrate that SSL3 is able to bind the extracellular domain of TLR2 and interfere with TLR2 function. The present study provides a novel mechanism of SSL3 in immune evasion of S. aureus via interfering with its recognition by innate immune cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Staphylococcal Superantigen-Like Protein 3 Binds to the Toll-Like Receptor 2 Extracellular Domain and Inhibits Cytokine Production Induced by Staphylococcus aureus, Cell Wall Component, or Lipopeptides in Murine Macrophages

et al. 2012

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“…Interestingly, the functions that have been discovered for SSLs so far have all been linked to immune evasion. SSL5 inhibits neutrophil extravasation (17,18) and phagocyte function (19,20), SSL7 binds IgA and inhibits complement (21), and SSL10 inhibits IgG1-mediated phagocytosis (22,23), blood coagulation (24), and the chemokine receptor CXCR4 (25). In addition to SSL3, also weak TLR2 inhibitory activity was observed for SSL4 (5), but it remains unknown whether that is its dominant function.…”

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confidence: 99%

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

Koymans

Feitsma

Brondijk

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Toll-like receptors (TLRs) are crucial in innate recognition of invading micro-organisms and their subsequent clearance. Bacteria are not passive bystanders and have evolved complex evasion mechanisms. Staphylococcus aureus secretes a potent TLR2 antagonist, staphylococcal superantigen-like protein 3 (SSL3), which prevents receptor stimulation by pathogen-associated lipopeptides. Here, we present crystal structures of SSL3 and its complex with TLR2. The structure reveals that formation of the specific inhibitory complex is predominantly mediated by hydrophobic contacts between SSL3 and TLR2 and does not involve interaction of TLR2-glycans with the conserved Lewis X binding site of SSL3. In the complex, SSL3 partially covers the entrance to the lipopeptide binding pocket in TLR2, reducing its size by ∼50%. We show that this is sufficient to inhibit binding of agonist Pam 2 CSK 4 effectively, yet allows SSL3 to bind to an already formed TLR2-Pam 2 CSK 4 complex. The binding site of SSL3 overlaps those of TLR2 dimerization partners TLR1 and TLR6 extensively. Combined, our data reveal a robust dual mechanism in which SSL3 interferes with TLR2 activation at two stages: by binding to TLR2, it blocks ligand binding and thus inhibits activation. Second, by interacting with an already formed TLR2-lipopeptide complex, it prevents TLR heterodimerization and downstream signaling.S. aureus | Toll-like receptor | immune evasion | innate immunity | crystal structure

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“…The natural ligand for CXCR4 is CXCL12, but SSL10's action clearly inhibited the chemotactic response of HeLa (cervical carcinoma) cells towards the natural ligand. 70 The class of bacterial protein SSL5 has been demonstrated to bind to the receptor for P-selectin glycoprotein-1 (PSGL-1), inhibiting rolling of neutrophils on a surface by acting as a decoy and thus hampering the interaction with its natural ligand, the P-selectin. The inhibitory action of SSL5, without any observed toxicity, was demonstrated in HL-60 leukemia cells since these cells express the receptor P-selectin glycoprotein-1 (PSGL-1).…”

Section: Bacteria-derived Anticancer Agentsmentioning

confidence: 99%

Microbial-based therapy of cancer: Current progress and future prospects

Bernardes¹,

Seruca²,

Chakrabarty³

et al. 2010

Bioengineered Bugs

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Staphylococcal Superantigen-like 10 Inhibits CXCL12-Induced Human Tumor Cell Migration

Abstract: Staphylococcal superantigen-like 10 is a potential lead in the development of new anticancer compounds preventing metastasis by targeting CXCR4.

Cited by 68 publications

References 48 publications

Staphylococcal Superantigen-Like Protein 3 Binds to the Toll-Like Receptor 2 Extracellular Domain and Inhibits Cytokine Production Induced by Staphylococcus aureus, Cell Wall Component, or Lipopeptides in Murine Macrophages

Staphylococcal Superantigen-Like Protein 3 Binds to the Toll-Like Receptor 2 Extracellular Domain and Inhibits Cytokine Production Induced by Staphylococcus aureus, Cell Wall Component, or Lipopeptides in Murine Macrophages

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

Microbial-based therapy of cancer: Current progress and future prospects

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