The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle

Jacobsen, Kristian M.; Keiding, Ulrik Bering; Clement, Lise L.; Schaffert, Eva S.; Rambaruth, N.D.S.; Johannsen, Mogens; Drickamer, Kurt; Poulsen, Thomas B.

doi:10.1039/c4md00512k

Cited by 41 publications

(56 citation statements)

References 12 publications

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“…Interestingly, the high affinity of synthetic brartemicin for the carbohydrate recognition domain of bovine Mincle dropped 30-fold when the monoester was used instead of the diester, while trehalose alone had 100-fold reduced affinity. 29 Thus, investigation of these non-lipid trehalose esters revealed a similar requirement for optimal binding to Mincle as found in our experiments comparing trehalose mono- and diesters with fatty acids with chain lengths between 14 and 22 carbon atoms.…”

Section: Discussionsupporting

confidence: 81%

“…Therefore, the recent report on the first soluble ligand for Mincle, namely brartemicin, is of considerable interest for functional studies. 29 Brartemicin, isolated from bacteria of the genus Nonomuraea (belonging to the family Streptosporangiaceae of the phylum Actinobacteria), is a diester of trehalose with two aromatic ring structures. Interestingly, the high affinity of synthetic brartemicin for the carbohydrate recognition domain of bovine Mincle dropped 30-fold when the monoester was used instead of the diester, while trehalose alone had 100-fold reduced affinity.…”

Section: Discussionmentioning

confidence: 99%

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Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, activation of macrophages in vitro and adjuvant activity in vivo

et al. 2016

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The T-cell adjuvanticity of mycobacterial cord factor trehalose 6,6'-dimycolate (TDM) is well established. The identification of the C-type lectin Mincle on innate immune cells as the receptor for TDM and its synthetic analogue trehalose 6,6'-dibehenate (TDB) has raised interest in development of synthetic Mincle ligands as novel adjuvants. Trehalose mono- (TMXs) and diesters (TDXs) with symmetrically shortened acyl chains [denoted by X: arachidate (A), stearate (S), palmitate (P), and myristate (M)] were tested. Upon stimulation of murine macrophages, G-CSF secretion and NO production were strongly augmented by all TDXs tested, in a wide concentration range. In contrast, the TMXs triggered macrophage activation only at high concentrations. Macrophage activation by all TDXs required Mincle, but was independent of MyD88. The superior capacity of TDXs for activating macrophages was paralleled by direct binding of TDXs, but not of TMXs, to a Mincle-Fc fusion protein. Insertion of a short polyethylene glycol between the sugar and acyl chain in TDS reduced Mincle-binding and macrophage activation. Immunization of mice with cationic liposomes containing the analogues demonstrated the superior adjuvant activity of trehalose diesters. Overall, immune activation in vitro and in vivo by trehalose esters of simple fatty acids requires two acyl chains of length and involves Mincle.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, activation of macrophages in vitro and adjuvant activity in vivo

et al. 2016

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“…For example, human Mincle recognizes glycerol monocorynomycolate derived from mycobacteria [17]. Brartemicin derived from actinomycetes binds to human and bovine Mincle [18]. Except for molecules having a similar structure with TDM, mannosyl fatty acids and β-gentiobiosyl glyceroglycolipids derived from Malassezia spp.…”

Section: Introductionmentioning

confidence: 99%

C-type Lectin Mincle Recognizes Glucosyl-diacylglycerol of Streptococcus pneumoniae and Plays a Protective Role in Pneumococcal Pneumonia

et al. 2016

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Among various innate immune receptor families, the role of C-type lectin receptors (CLRs) in lung protective immunity against Streptococcus pneumoniae (S. pneumoniae) is not fully defined. We here show that Mincle gene expression was induced in alveolar macrophages and neutrophils in bronchoalveolar lavage fluids of mice and patients with pneumococcal pneumonia. Moreover, S. pneumoniae directly triggered Mincle reporter cell activation in vitro via its glycolipid glucosyl-diacylglycerol (Glc-DAG), which was identified as the ligand recognized by Mincle. Purified Glc-DAG triggered Mincle reporter cell activation and stimulated inflammatory cytokine release by human alveolar macrophages and alveolar macrophages from WT but not Mincle KO mice. Mincle deficiency led to increased bacterial loads and decreased survival together with strongly dysregulated cytokine responses in mice challenged with focal pneumonia inducing S. pneumoniae, all of which was normalized in Mincle KO mice reconstituted with a WT hematopoietic system. In conclusion, the Mincle-Glc-DAG axis is a hitherto unrecognized element of lung protective immunity against focal pneumonia induced by S. pneumoniae.

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“…Overview of microbial and endogenous ligands of Syk-coupled CLRs TDM or TDB. The recent interest in Mincle ligands for adjuvant development(78)(79)(80) has engendered the chemical synthesis of multiple glycolipids, which help to determine the requirements for receptor binding and macrophage activation(81)(82)(83)(84). Different from cord factor binding, recognition of the nucleoprotein SAP130 is Ca 2+ -independent(6).…”

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confidence: 99%

Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors

Ostrop

Lang

2017

The Journal of Immunology

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conducted on CLR assigned to the so-called Dectin-1 or Dectin-2 clusters, localized within 51 the NK cell gene cluster on human chromosome 12 or mouse chromosome 6 (1-3). Several 52 excellent reviews on the function of these CLR in anti-microbial defense and homeostasis are 53 available (4, 5). In this review we summarize the current knowledge about signaling 54 downstream of the activating CLR Dectin-1 (Clec7a), Dectin-2 (human Clec6a, mouse 55 Clec4n), Mincle (Clec4e) and Mcl (Clec4d) that is largely dependent on the kinase spleen 56 tyrosine kinase (Syk). Table I provides an overview of defined ligands and microorganisms 57 bound by this group of PRR. In addition to microbial carbohydrate and glycolipid structures 58 acting as PAMP, several CLR bind endogenous ligands such as SAP130 released by dying 59 cells or cholesterol crystals. Thus, these CLR are involved in homeostatic responses and 60 inflammatory conditions (6-9), in addition to host response to pathogens and commensals (10-61 (Fig. 1). 103 Syk-Card9 coupled CLR is observed across cell-types and species, promoting the 111 differentiation of IL-17-producing CD4+ T cells (23, 24, 26, 27). Remarkably, to date there is 112 only very limited information about the effects of combined stimulation of CLR and TLR 113 pathways on global gene expression. 114

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The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle

Abstract: We demonstrate that the natural product brartemicin, a newly discovered inhibitor of cancer cell invasion, is a high-affinity ligand of the carbohydrate-recognition domain (CRD) of the C-type lectin mincle.

Cited by 41 publications

References 12 publications

Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, activation of macrophages in vitro and adjuvant activity in vivo

Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, activation of macrophages in vitro and adjuvant activity in vivo

C-type Lectin Mincle Recognizes Glucosyl-diacylglycerol of Streptococcus pneumoniae and Plays a Protective Role in Pneumococcal Pneumonia

Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors

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