Human C-Type Lectins, MGL, DC-SIGN and Langerin, Their Interactions With Endogenous and Exogenous Ligand Patterns

Chiodo, Fabrizio; Haas, Aram de; Vliet, Sandra J. van; Kooyk, Yvette van

doi:10.1016/b978-0-12-819475-1.00090-0

Cited by 3 publications

(3 citation statements)

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“…We also observe a significant increase in global sialylation of N -glycans through both MS and lectin staining. Both the expression of Tn, STn, and the more general increased expression of especially 2,6 linked sialic acids on N -linked glycans are known to induce immune-tolerance through interactions with the C-type lectin MGL and members of the family of Siglecs ( van Vliet et al 2006 ; Crocker et al 2007 ; Mathiesen et al 2018 ; Chiodo et al 2021 ). Accordingly, increased expression of Tn and sialylation in tumors has been shown to induce immune escape, metastasis, and tumor formation ( Büll et al 2014 ; Ju et al 2014 ; Radhakrishnan et al 2014 ; Bhide and Colley 2017 ).…”

Section: Discussionmentioning

confidence: 99%

CRISPR-screen identifies ZIP9 and dysregulated Zn2+ homeostasis as a cause of cancer-associated changes in glycosylation

et al. 2023

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In epithelial cancers, truncated O-glycans, such as the Thomson-nouveau antigen (Tn) and its sialylated form (STn), are up-regulated on the cell surface and associated with poor prognosis and immunological escape. Recent studies have shown that these carbohydrate epitopes facilitate cancer development and can be targeted therapeutically; however, the mechanism underpinning their expression remains unclear. To identify genes directly influencing the expression of cancer-associated O-glycans, we conducted an unbiased, positive-selection, whole genome CRISPR knockout-screen using monoclonal antibodies against Tn and STn. We show that knockout of the Zn2+-transporter SLC39A9 (ZIP9), alongside the well-described targets C1GALT1 (C1GalT1) and its molecular chaperone, C1GALT1C1 (COSMC), results in surface-expression of cancer-associated O-glycans. No other gene perturbations were found to reliably induce O-glycan truncation. We furthermore show that ZIP9 knockout affects N-linked glycosylation, resulting in up-regulation of oligo-mannose, hybrid-type, and α2,6-sialylated structures as well as down-regulation of tri- and tetra-antennary structures. Finally, we demonstrate that accumulation of Zn2+ in the secretory pathway coincides with cell-surface presentation of truncated O-glycans in cancer tissue, and that over-expression of COSMC mitigates such changes. Collectively, the findings show that dysregulation of ZIP9 and Zn2+ induces cancer-like glycosylation on the cell surface by affecting the glycosylation machinery.

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Section: Discussionmentioning

confidence: 99%

CRISPR-screen identifies ZIP9 and dysregulated Zn2+ homeostasis as a cause of cancer-associated changes in glycosylation

et al. 2023

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“…The C-type lectin receptors (CLR) family are pattern recognition receptors that play an important role in maintaining host tissue homeostasis but are also critically important in host-microbe interactions (Chiodo et al 2021). The family of CLRs consists of many different subgroups harbouring several different receptors that all share a calcium-dependent carbohydrate-recognition domain (CRD) (Weis et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Human Milk Oligosaccharide 2’-fucosyllactose inhibits ligand binding to C-type lectin DC-SIGN but not to Langerin

Mukherjee

Somovilla

Chiodo

et al. 2022

Preprint

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Human milk oligosaccharides (HMOs) and its most abundant component, 2'-Fucosyllactose (2'-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2'-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2'-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Leb) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2'-FL was not detected for another C-type lectin, Langerin, evolutionary similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2'-FL inhibits the binding of DC-SIGN to Leb. Molecular dynamics (MD) simulations show that 2'-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Leb has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. 2'-FL may have a reduced entropic penalty due to its preorganized state compared to Leb, and it has lower binding enthalpy, suggesting better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2'-FL may replace Leb from its binding pocket in DC-SIGN. MD simulations also showed that 2'-FL does not bind to Langerin. Our studies confirm 2'-FL as a specific ligand for DC-SIGN and suggest that 2'-FL can replace other DC-SIGN ligands from its binding pocket during ligand-receptor interactions in possible immunomodulatory processes.

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“…The C-type lectin receptor (CLR) family are pattern recognition receptors that play an important role in maintaining the host tissue homeostasis but are also critically important in host-microbe interactions [ 1 ] The family of CLRs consists of many different subgroups harbouring several different receptors that all share a calcium-dependent carbohydrate-recognition domain (CRD) [ 2 ]. CLRs respond to a wide variety of ligands, both from endogenous and exogenous origins, as (glyco)lipids, (glyco)proteins, or glycans [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin

Mukherjee

Somovilla

Chiodo

et al. 2022

IJMS

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Human milk oligosaccharides (HMOs) and their most abundant component, 2′-Fucosyllactose (2′-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2′-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2′-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Leb) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2′-FL was not detected for another C-type lectin, langerin, which is evolutionarily similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2′-FL inhibits the binding of DC-SIGN to Leb. Molecular dynamic (MD) simulations show that 2′-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Leb has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. Our hypothesis is that 2′-FL may have a reduced entropic penalty due to its preorganized state, compared to Leb, and it has a lower binding enthalpy, suggesting a better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2′-FL may replace Leb from its binding pocket in DC-SIGN. The MD simulations also showed that 2′-FL does not bind to langerin. Our studies confirm 2′-FL as a specific ligand for DC-SIGN and suggest that 2′-FL can replace other DC-SIGN ligands from its binding pocket during the ligand-receptor interactions in possible immunomodulatory processes.

show abstract

Human C-Type Lectins, MGL, DC-SIGN and Langerin, Their Interactions With Endogenous and Exogenous Ligand Patterns

Cited by 3 publications

References 185 publications

CRISPR-screen identifies ZIP9 and dysregulated Zn2+ homeostasis as a cause of cancer-associated changes in glycosylation

CRISPR-screen identifies ZIP9 and dysregulated Zn2+ homeostasis as a cause of cancer-associated changes in glycosylation

Human Milk Oligosaccharide 2’-fucosyllactose inhibits ligand binding to C-type lectin DC-SIGN but not to Langerin

Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin

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