S100A15, an Antimicrobial Protein of the Skin: Regulation by E. coli through Toll-Like Receptor 4

Büchau, Amanda S.; Hassan, Mohamed; Kukova, Gabriela; Lewerenz, V.; Kellermann, Sabine; Würthner, Jens U.; Wolf, Ronald; Walz, Markus; Gallo, Richard L.; Ruzicka, Thomas

doi:10.1038/sj.jid.5700946

Cited by 75 publications

(65 citation statements)

References 50 publications

(83 reference statements)

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“…Antibacterial activity attributable to the zinc-binding motifs could require the presence of the calprotectin complex. Yet S100 family members other than calprotectin show antimicrobial activity, including S100A7, S100A12, and S100A15 (45)(46)(47). These S100 protein family members do not possess an extended C-terminal domain with an HHH motif, nor do they appear to form heterodimers.…”

Section: Discussionmentioning

confidence: 99%

Calprotectin S100A9 Calcium-binding Loops I and II Are Essential for Keratinocyte Resistance to Bacterial Invasion

Champaiboon

Sappington

Guenther

et al. 2009

Journal of Biological Chemistry

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Epithelial cells expressing calprotectin, a heterodimer of S100A8 and S100A9 proteins, are more resistant to bacterial invasion. To determine structural motifs that affect resistance to bacterial invasion, mutations were constructed in S100A9 targeting the calcium-binding loops I and II (E36Q, E78Q, E36Q,E78Q) and the C terminus (S100A9 1-99 and S100A9 1-112 ), which contains putative antimicrobial zinc-binding and phosphorylation sites. The S100A8 and mutated S100A9 encoding plasmids were transfected into calprotectin-negative KB carcinoma cells. All transfected cells (except KB-sham) expressed 27E10-reactive heterodimers. In bacterial invasion assays with Listeria monocytogenes and Salmonella enterica serovar Typhimurium (Salmonella typhimurium), cell lines expressing S100A8 in complex with S100A9 E36Q , S100A9 E78Q , S100A9 1-99 , or S100A9 1-112 mutants or the S100A9 1-114 (full-length) calprotectin resisted bacterial invasion better than KB-sham. When compared with KB-S100A8/A9 1-114 , cells expressing truncated S100A9 1-99 or S100A9 1-112 with S100A8 also showed increased resistance to bacterial invasion. In contrast, glutamic acid residues 36 and 78 in calcium-binding loops I and II promote resistance in epithelial cells, because cells expressing S100A9 E36Q,E78Q with S100A8 were unable to resist bacterial invasion. Mutations in S100A9 E36Q, E78Q were predicted to cause loss of the calcium-induced positive face in calprotectin, reducing interactions with microtubules and appearing to be crucial for keratinocyte resistance to bacterial invasion.

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Section: Discussionmentioning

confidence: 99%

Calprotectin S100A9 Calcium-binding Loops I and II Are Essential for Keratinocyte Resistance to Bacterial Invasion

Champaiboon

Sappington

Guenther

et al. 2009

Journal of Biological Chemistry

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“…In addition to CP, several other S100 proteins, including S100A12, S100A7, and S100A15, have been suggested to contribute to host defense through the sequestration of essential transition metal nutrients (43)(44)(45). Numerous studies of Zn binding and crystal structures for zinc-bound S100B, S100A7, and S100A12 are available, but little is known about the Mn-binding properties of S100 proteins (15)(16)(17)46).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Damo

Kehl-Fie

Sugitani

et al. 2013

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

337

594

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The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn 2+ and Zn 2+ with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn 2+ sequestration. The asymmetry of the CP heterodimer creates a single Mn 2+ -binding site from six histidine residues, which distinguishes CP from all other Mn 2+ -binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn 2+ and Zn 2+ being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn 2+ sequestration. These data establish the importance of Mn 2+ sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.bacterial pathogenesis | Staphylococcus aureus | antibiotic resistance | protein crystal structure | isothermal titration calorimetry B acterial pathogens are a significant threat to global public health. This threat is compounded by the fact that these organisms are rapidly becoming resistant to all relevant antimicrobials. Of particular note is the recent emergence of antibiotic-resistant strains of Staphylococcus aureus as a leading cause of bacterial infection in the United States (1) and arguably the most important threat to the public health of the developed world. Consequently, the identification of therapeutics to treat bacterial pathogens is paramount to our continued ability to limit this infectious threat.One promising area of potential therapeutic development involves targeting bacterial access to essential transition metals. This strategy is based on the fact that all bacterial pathogens require these nutrient metals to colonize their hosts (2-5). In vertebrates, the bacterial need for nutrient transition metals is counteracted by the sequestration of these metals by the host. This limitation of essential nutrients, termed "nutritional immunity," is a potent defense against infection (6). Although a variety of metals is required for microbial growth, studies of nutritional immunity have been primarily restricted to the struggle for iron (Fe) between host and pathogen (7-9).An innate immune factor, calprotectin (CP), is abundant in neutrophils and plays a key role in nutritional immunity. CP can be found at sites of infection in excess of 1 mg/mL and is required for the control of a number of medically relevant bacteria and fungi including S. aureus, Candida albicans, and Aspergillus fumigates (10-14). The antimicrobial activity of CP is due to the chelation of the essential nutrients Zn 2+ (Zn) and Mn 2+ (Mn), which results in bacterial metal starvation and is reversed by the addition of these metals in excess (11, 13). Moreover, CP-deficient mice have increased microbial burdens following systemic challenge, und...

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“…S100 proteins are low molecular weight cationic proteins characterized by two calcium-binding EF-hand motifs (Donato, 2001;Eckert et al, 2004). They are involved in a variety of cellular processes such as calcium-dependent cell signalling, cell growth and differentiation, cell cycle regulation, and antimicrobial defense (Eckert et al, 2004;Marenholz et al, 2004;Gläser et al, 2005;Bü chau et al, 2007;Corbin et al, 2008). So far, microbicidal activity has been described for S100A7c (psoriasin), calprotectin, which is a heterodimeric complex of S100A8 (calgranulin A, MRP8) and S100A9 (calgranulin B, MRP14), S100A12 (calgranulin C), and S100A15 (Sohnle et al, 2000;Cole et al, 2001;Gläser et al, 2005;Bü chau et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Antimicrobial Heterodimer S100A8/S100A9 (Calprotectin) Is Upregulated by Bacterial Flagellin in Human Epidermal Keratinocytes

Abtin

Eckhart

Gläser

et al. 2010

Journal of Investigative Dermatology

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Antimicrobial peptides (AMPs) have a central role in the innate immune system of the skin. Epidermal keratinocytes (KCs) express numerous such peptides either constitutively or in response to exposure to microbial compounds. Here, we investigated the regulation of S100A8 (calgranulin A) and S100A9 (calgranulin B), which form an antimicrobial heterodimeric complex also known as calprotectin, in KCs. Culture supernatants of gram-negative bacteria, but not of gram-positive bacteria nor of the yeast Candida albicans, triggered the expression of S100A8 and S100A9. To identify pathogen-associated molecular patterns (PAMPs) responsible for the upregulation of S100A8 and S100A9, KCs were stimulated with ligands for Toll-like receptors (TLRs). Quantitative real-time PCR (qRT-PCR) analysis revealed that the TLR5 ligand flagellin increased the mRNA expression of both S100A8 and S100A9. Supernatant from wild-type (WT) Escherichia coli, but not from a flagellin-deficient E. coli strain (ΔFliC), induced S100A8 and S100A9 protein production in KCs. Moreover, small interfering RNA-mediated knockdown of TLR5 expression suppressed the ability of KCs to upregulate S100A8 and S100A9 mRNA expression in response to E. coli supernatant. Like in cell culture, stimulation of human skin explants with E. coli induced the expression of S100A8 and S100A9. Our data suggest that bacterial flagellin induces the upregulation of S100A8/S100A9 via a TLR5-dependent mechanism in epidermal KCs.

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S100A15, an Antimicrobial Protein of the Skin: Regulation by E. coli through Toll-Like Receptor 4

Cited by 75 publications

References 50 publications

Calprotectin S100A9 Calcium-binding Loops I and II Are Essential for Keratinocyte Resistance to Bacterial Invasion

Calprotectin S100A9 Calcium-binding Loops I and II Are Essential for Keratinocyte Resistance to Bacterial Invasion

Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

The Antimicrobial Heterodimer S100A8/S100A9 (Calprotectin) Is Upregulated by Bacterial Flagellin in Human Epidermal Keratinocytes

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