Analysis of CD44-Hyaluronan Interactions in an Artificial Membrane System

Wolny, Patricia M.; Banerji, Suneale; Gounou, Céline; Brisson, Alain; Day, Anthony J.; Jackson, David G.; Richter, Ralf P.

doi:10.1074/jbc.m110.137562

Cited by 199 publications

(147 citation statements)

References 62 publications

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“…Colloidal Probe RICM-This microinterferometic technique measures the height at which a colloidal probe hovers above a transparent planar substrate with a resolution of a few nm. RICM was used to measure the thickness of HA films that were assembled on bare or gold-coated glass coverslips, using custom-built liquid cells (41,45) (see supplemental material for details).…”

Section: Methodsmentioning

confidence: 99%

The Inflammation-associated Protein TSG-6 Cross-links Hyaluronan via Hyaluronan-induced TSG-6 Oligomers

Baranova

Nilebäck

Haller³

et al. 2011

Journal of Biological Chemistry

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190

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Tumor necrosis factor-stimulated gene-6 (TSG-6) is a hyaluronan (HA)-binding protein that plays important roles in inflammation and ovulation. TSG-6-mediated cross-linking of HA has been proposed as a functional mechanism (e.g. for regulating leukocyte adhesion), but direct evidence for cross-linking is lacking, and we know very little about its impact on HA ultrastructure. Here we used films of polymeric and oligomeric HA chains, end-grafted to a solid support, and a combination of surface-sensitive biophysical techniques to quantify the binding of TSG-6 into HA films and to correlate binding to morphological changes. We find that full-length TSG-6 binds with pronounced positive cooperativity and demonstrate that it can cross-link HA at physiologically relevant concentrations. Our data indicate that cooperative binding of full-length TSG-6 arises from HA-induced protein oligomerization and that the TSG-6 oligomers act as cross-linkers. In contrast, the HA-binding domain of TSG-6 (the Link module) alone binds without positive cooperativity and weaker than the full-length protein.Both the Link module and full-length TSG-6 condensed and rigidified HA films, and the degree of condensation scaled with the affinity between the TSG-6 constructs and HA. We propose that condensation is the result of protein-mediated HA crosslinking. Our findings firmly establish that TSG-6 is a potent HA cross-linking agent and might hence have important implications for the mechanistic understanding of the biological function of TSG-6 (e.g. in inflammation). Hyaluronan (HA)3 is a structurally simple and linear polysaccharide. It is ubiquitous in the extracellular matrix of vertebrates and plays important roles in numerous physiological and pathological processes, such as inflammation, fertilization, embryogenesis, tumor development, osteoarthritis, and atherosclerosis (1, 2). HA is considered a "pericellular cue" (3) (i.e. it serves as a versatile scaffold within which other molecules are organized and regulated). A number of proteins, called hyaladherins (4), can bind to the flexible HA chains and engender self-assembly into large and hydrated multimolecular complexes (5-7).The secreted product of tumor necrosis factor-stimulated gene-6 (TSG-6) (8, 9) is of particular importance for the formation and remodeling of HA-rich pericellular coats (10, 11) and extracellular matrices (12). There is little or no constitutive expression of TSG-6 in most adult tissues (with the exception of bone marrow (13) and epidermis (14)). Expression is elevated in response to stimulation with proinflammatory mediators or certain growth factors (8, 9, 15-18), and TSG-6 is detected in the context of many inflammatory diseases (19,20) and in inflammation-like processes, such as ovulation (21,22). TSG-6 is composed mainly of two contiguous domains, a Link module and a CUB module (8,17,23,24). The Link module is conserved among members of the hyaladherin family (4) and is essential for binding to HA (23). Administration of recombinant human TSG-6 Link module (L...

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Section: Methodsmentioning

confidence: 99%

The Inflammation-associated Protein TSG-6 Cross-links Hyaluronan via Hyaluronan-induced TSG-6 Oligomers

Baranova

Nilebäck

Haller³

et al. 2011

Journal of Biological Chemistry

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190

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“…Hence, contributions from CD44 and TLR2 appeared to be required for MDa HA to block OPC maturation, whereas bHAf actions specifically required an interaction with TLR4. Notably, binding of larger-sized HA appears to be stabilized by multivalent interactions with CD44, whereas smaller HAf has distinct binding properties (44). Polydispersed HA of larger sizes in human milk also requires both CD44 and TLR4 to mediate their biological effects, whereas 35-kDa HAf works independently of CD44 (41).…”

Section: Foxo3 Expression Is Markedly Increased In Oligodendroglia Inmentioning

confidence: 99%

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Srivastava¹,

Diba²,

Dean³

et al. 2018

Journal of Clinical Investigation

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ers by interactions of FoxO3 with the chromatin-remodeling factor Brg1 and the TF Olig2, which are involved in control of OPC differentiation (14-16). Hence, central myelination failure is regulated by a noncanonical TLR4/AKT/FoxO3 signaling pathway utilized by bHAf to induce a tolerance-like state that selectively constrains OPC maturation and myelination. ResultsNeonatal hypoxic-ischemic WMI promotes MDa HA depolymerization. To investigate the status of MDa HA in chronic neonatal WMI, we employed our preterm-equivalent rat hypoxia-ischemia (H-I) model, which generates myelination failure and replicates key features of human WMI ( Figure 1A) (17). MDa HA turnover in the ECM after H-I was visualized with a biotinylated HA-binding protein (HABP) and costained with glial fibrillary acidic protein (GFAP) as a marker of WMI. Unlike in age-matched uninpro-myelination signal (13). This tolerance-like action of bHAf was mediated through TLR4 but not via CD44 or TLR2. As in TLR4-mediated IT, bHAf 's influence on myelination was reversible when MDa HA depolymerization was attenuated or bHAf was removed. AKT desensitization was similarly reversible in vivo in neonatal WMI. Moreover, bHAf actions were mediated via a noncanonical TRIF-dependent pathway, also involved in IT, rather than the canonical MyD88 arm of TLR4 signaling. AKT desensitization resulted in maturation-dependent activation of the FoxO3 transcription factor (TF), which selectively constrained preOL maturation in a bHAf-dependent fashion. A role for activated FoxO3 in human myelination failure was supported by selective localization of nuclear FoxO3 to OPCs in human preterm WMI and multiple sclerosis (MS) plaques. bHAf-mediated OPC maturation arrest appears to be regulated at the FoxO3 and myelin basic protein (MBP) promot- (Contralateral). Only the lesion group had a significant reduction in HA recovery. (E) Incubation of MDa HA with the lesion lysate generated HAf below ~650 kDa. Lesion-lysate activity was sensitive to heat inactivation but insensitive to deferoxamine (50 μM). B and C: control n = 2; H-I n = 4 animals for each age group (P4 and P14). D: n = 6 (H-I), n = 5 (control), and n = 4 (hypoxia) animals (P7). E: n = 4 separate experiments on 4 different animals at P4 after H-I at P3; one representative experiment is shown. *P < 0.05 by ANOVA. Mean ± SD. Scale bars: 300 μm (B and C). The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 0 2 7 jci.orgVolume 128 Number 5 May 2018 with MBP-labeled oligodendrocytes (Supplemental Figure 2A). To confirm de novo progressive myelin generation, we undertook ultrastructural studies that identified axons wrapped with multilamellar myelin sheaths ( Figure 2B). In contrast to vehicle-treated slices, which displayed robust myelination of the corpus callosum, slices incubated with MDa HA until 21 days in vitro (DIV21) displayed a pronounced reduction in myelinated axons ( Figure 2C). Myelination failure was not related to decreased OPC survival, since MDa HA treatment did not enhance OPC degeneratio...

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“…Each Anx5ZZ was shown to bind two IgGs, in agreement with the fact that Anx5ZZ contains a tandem Z repeat. The affinity coupling of IgGs to ZZ domains presents several major advantages; not only it is highly efficient and complete, but it involves un-modified IgGs, avoids possible alteration by chemical modification, and maintains an optimal orientation of IgGs towards their target site [20,21]. In comparison, the covalent coupling of IgGs to lipid hydrazides via carbohydrate residues located in Fc domains constitutes another approach allowing the control of the IgG orientation, yet with low yield [15].…”

Section: Discussionmentioning

confidence: 99%

“…The Anx5ZZ fusion protein was produced by fusing rat Anx5 with the ZZ domain of protein A from S. aureus as described in Wolny et al [21]. The Anx5ZZ-SH protein was produced by fusing Anx5-SH, produced as described in Bérat et al [25], to a ZZ domain, as described for Anx5ZZ.…”

Section: Preparation Of Annexin Proteinsmentioning

confidence: 99%

“…1). The proposed strategy presents several potential advantages: (1) the Anx5ZZ adaptor protein was constructed with the ZZ domain exposed on the face of Anx5 opposite to its membrane-binding face, so that Anx5ZZ proteins combine properties of membrane binding and IgG binding [20]; (2) this construction ensures an optimal orientation of IgG molecules [20,21] so that their antigen-binding domains are exposed towards their target epitopes; (3) this system is in principle versatile, allowing the functionalization of liposomes with IgG subtypes that are recognized by protein A.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Platform of Antibody-Presenting Liposomes

et al. 2012

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Antibody-presenting liposomes present high interest as drug delivery systems. The association of antibodies to liposomes is usually realized by covalent coupling of IgGs or their antigen-binding fragments to lipid polar head groups by means of hetero-bifunctional crosslinkers. We present here an original platform of IgGpresenting liposomes which is based on a fusion protein between Annexin-A5 (Anx5) and the IgG-binding ZZ repeat derived from Staphylococcus aureus protein A. The Anx5ZZ fusion protein acts as a bi-functional adaptor that anchors IgGs to liposomes in a non covalent and highly versatile manner. The interactions between IgGs, Anx5ZZ and liposomes were characterized by PAGE, dynamic light scattering and fluorescence quenching assays, establishing that binding of Anx5ZZ to IgGs and of Anx5ZZ-IgG complexes to liposomes is complete with stoichiometric amounts of each species. We found that the sequence of assembly is important and that Anx5ZZ-IgG complexes need to be formed first in solution and then adsorbed to liposomes in order to avoid aggregation. The targeting capacity of Anx5ZZ-IgG-functionalized liposomes was demonstrated by electron microscopy on an ex vivo model system of atherosclerotic plaques. This study shows that the Anx5ZZ adaptor constitutes an efficient platform for functionalizing liposomes with IgGs. This platform may present potential applications in molecular imaging and drug delivery.

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Analysis of CD44-Hyaluronan Interactions in an Artificial Membrane System

Cited by 199 publications

References 62 publications

The Inflammation-associated Protein TSG-6 Cross-links Hyaluronan via Hyaluronan-induced TSG-6 Oligomers

The Inflammation-associated Protein TSG-6 Cross-links Hyaluronan via Hyaluronan-induced TSG-6 Oligomers

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Development of a Platform of Antibody-Presenting Liposomes

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