Showing papers on "Galectin published in 2018"

Galectins at a glance.

Abstract: Galectins are carbohydrate-binding proteins that are involved in many physiological functions, such as inflammation, immune responses, cell migration, autophagy and signalling. They are also linked to diseases such as fibrosis, cancer and heart disease. How such a small family of only 15 members can have such widespread effects remains a conundrum. In this Cell Science at a Glance article, we summarise recent literature on the many cellular activities that have been ascribed to galectins. As shown on the accompanying poster, these include carbohydrate-independent interactions with cytosolic or nuclear targets and carbohydrate-dependent interactions with extracellular glycoconjugates. We discuss how these intra- and extracellular activities might be linked and point out the importance of unravelling molecular mechanisms of galectin function to gain a true understanding of their contributions to the physiology of the cell. We close with a short outlook on the organismal functions of galectins and a perspective on the major challenges in the field.

Role of Galectins in Tumors and in Clinical Immunotherapy

Abstract: Galectins are glycan-binding proteins that contain one or two carbohydrate domains and mediate multiple biological functions. By analyzing clinical tumor samples, the abnormal expression of galectins is known to be linked to the development, progression and metastasis of cancers. Galectins also have diverse functions on different immune cells that either promote inflammation or dampen T cell-mediated immune responses, depending on cognate receptors on target cells. Thus, tumor-derived galectins can have bifunctional effects on tumor and immune cells. This review focuses on the biological effects of galectin-1, galectin-3 and galectin-9 in various cancers and discusses anticancer therapies that target these molecules.

Human Milk Oligosaccharides as Essential Tools for Basic and Application Studies on Galectins

Abstract: It is now recognized that human milk oligosaccharides (HMOs) can function both as prebiotics and as decoy receptors that inhibit the attachment of pathogenic microorganisms to the colonic mucosa. They can also act as immune modulators and as colonic maturation stimulators in breast-fed infants. These functions could be mediated by biological interaction between a variety of HMOs and lectins including galectins, selectins and siglecs. There are more than 100 HMOs; they have structural units such as H type 1: Fucα1-2Galβ1-3GlcNAc, Lewis a: Galβ1-3(Fucα1-4)GlcNAc, Lewis b: Fucα1-2Galβ1-3(Fucα1-4)GlcNAc, Lewis x: Galβ1-4(Fuc α1-3)GlcNAc, sialyl Lewis a: Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAc, and sialyl Lewis x: Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc. It can be expected that these units may be utilized as tools for studies on the sugar-binding specificities of lectins including galectins, monoclonal antibodies, virus capsid proteins and bacterial toxins. This mini-review presents the dataset of comprehensive HMO structures, including recently clarified ones, in tabular form, for its utilization in such studies, including those of carbohydratebinding specificity of galectins. In addition, this review introduces recent in vivo and clinical studies, which may be relevant to the biological functions and future utilization of HMOs. A. Introduction Human milk contains around 60 g/L of lactose (Galβ1-4Glc), as well as 12–13 g/L of a variety of milk oligosaccharides in mature milk and 22–24 g/L in colostrum. Whereas human milk oligosaccharides (HMOs) comprise several monosaccharide components, such as glucose (Glc), N-acetylglucosamine (GlcNAc), galactose (Gal), fucose (Fuc) and N-acetylneuraminic acid (Neu5Ac), they always have a lactose unit at their reducing ends. Although by 2009 the structures of about 115 HMOs had been characterized and clarified based on 13 core series (1, 2), a comprehensive database, including large novel structures, had not been described. When breast-fed infants consume their mother’s milk, the majority of the HMOs are not digested and absorbed within the small intestine and therefore reach the infant’s colon. It has been suggested from in vitro studies that the HMOs function as prebiotics and decoy receptors, inhibiting the attachment of certain types of pathogenic microorganisms to the colonic mucosa, and as modulators of colonic epithelial maturation (1, 3–5). It has been also shown that some strains of Bifidobacterium bifidum, B. longum ssp. infantis, and B. breve are able to grow in medium containing HMOs as the only carbon source (6–8). It has been also clarified that B. bifidum is characterized by a unique metabolic pathway in which HMOs are digested by several extracellular and intracellular glycosidases (7). Notably, low concentrations of some HMOs are detected in plasma from venous blood after the consumption of breast milk (9, 10). Thus, it appears that a minor part of HMOs is absorbed within the small intestine and enters the circulation. It is possible that those HMOs have immune modulation effects such as anti-inflammation, as suggested by in vitro studies using blood leukocytes (11), platelets and endothelial cells (12). It can be assumed that the recognition of those HMOs by some endogenous lectins including galectins, selectins and siglecs is related to those biological activities of HMOs. Therefore, studies on the interaction between HMOs and lectins may generate useful information relating to the utilization of HMOs in therapy, such as immunomodulation and inhibition of the establishment of infection. Notably, as some HMOs have been recently produced on an industrial scale (13), these studies combined with advances in the industrial production of HMOs may in near future open up the possibility of the utilization of HMOs for the treatment and/or prevention of human diseases. HMOs consist of more than 100 individual molecules. They have been so far utilized as tools for studies on the sugar binding MINIREVIEW doi: 10.4052/tigg.1734.1SE (Article for special issue on Galectins)

The Role of Galectins as Modulators of Metabolism and Inflammation.

Abstract: Galectins are β-galcotosid-binding lectins. The function of galectins varies with their tissue-specific and subcellular location, and their binding to carbohydrates makes them key players in several intra- and extracellular processes where they bind to glycosylated proteins and lipids. In humans, there are 12 identified galectins, some with tissue-specific distribution. Galectins are found inside cells and in the nucleus, cytosol, and organelles, as well as extracellularly. Galectin-1, -2, -3, -4, -7, -8, -9, and -12 can all induce T-cell apoptosis and modulate inflammation. In the context of metabolic control and loss of the same in, for example, diabetes, galectin-1, -2, -3, -9, and -12 are especially interesting. This review presents information on galectins relevant to the control of inflammation and metabolism and the potential to target galectins for therapeutic purposes.

Molecular mechanism to recruit galectin-3 into multivesicular bodies for polarized exosomal secretion.

Abstract: The beta-galactoside binding lectin galectin-3 (Gal3) is found intracellularly and in the extracellular space. Secretion of this lectin is mediated independently of the secretory pathway by a not yet defined nonclassical mechanism. Here, we found Gal3 in the lumen of exosomes. Superresolution and electron microscopy studies visualized Gal3 recruitment and sorting into intraluminal vesicles. Exosomal Gal3 release depends on the endosomal sorting complex required for transport I (ESCRT-I) component Tsg101 and functional Vps4a. Either Tsg101 knockdown or expression of dominant-negative Vps4aE228Q causes an intracellular Gal3 accumulation at multivesicular body formation sites. In addition, we identified a highly conserved tetrapeptide P(S/T)AP motif in the amino terminus of Gal3 that mediates a direct interaction with Tsg101. Mutation of the P(S/T)AP motif results in a loss of interaction and a dramatic decrease in exosomal Gal3 secretion. We conclude that Gal3 is a member of endogenous non-ESCRT proteins which are P(S/T)AP tagged for exosomal release.

Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling.

Abstract: Glycosylation is a very frequent and functionally important post-translational protein modification that undergoes profound changes in cancer. Growth and death factor receptors and plasma membrane glycoproteins, which upon activation by extracellular ligands trigger a signal transduction cascade, are targets of several molecular anti-cancer drugs. In this review, we provide a thorough picture of the mechanisms bywhich glycosylation affects the activity of growth and death factor receptors in normal and pathological conditions. Glycosylation affects receptor activity through three non-mutually exclusive basic mechanisms: (1) by directly regulating intracellular transport, ligand binding, oligomerization and signaling of receptors; (2) through the binding of receptor carbohydrate structures to galectins, forming a lattice thatregulates receptor turnover on the plasma membrane; and (3) by receptor interaction with gangliosides inside membrane microdomains. Some carbohydrate chains, for example core fucose and β1,6-branching, exert a stimulatory effect on all receptors, while other structures exert opposite effects on different receptors or in different cellular contexts. In light of the crucial role played by glycosylation in the regulation of receptor activity, the development of next-generation drugs targeting glyco-epitopes of growth factor receptors should be considered a therapeutically interesting goal.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

Abstract: The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for β-galactosides. The galectin–glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins’ action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

Galectins as Molecular Targets for Therapeutic Intervention.

Abstract: Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and pathologies, galectins have become a focus of therapeutic discovery for clinical intervention against cancer, among other pathological disorders. In this review, we focus on understanding galectin structure-function relationships, their mechanisms of action on the molecular level, and targeting them for therapeutic intervention against cancer.

Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans.

Abstract: Leukocytes are coated with a layer of heterogeneous carbohydrates (glycans) that modulate immune function, in part by governing specific interactions with glycan-binding proteins (lectins). Although nearly all membrane proteins bear glycans, the identity and function of most of these sugars on leukocytes remain unexplored. Here, we characterize the N-glycan repertoire (N-glycome) of human tonsillar B cells. We observe that naive and memory B cells express an N-glycan repertoire conferring strong binding to the immunoregulatory lectin galectin-9 (Gal-9). Germinal center B cells, by contrast, show sharply diminished binding to Gal-9 due to upregulation of I-branched N-glycans, catalyzed by the β1,6-N-acetylglucosaminyltransferase GCNT2. Functionally, we find that Gal-9 is autologously produced by naive B cells, binds CD45, suppresses calcium signaling via a Lyn-CD22-SHP-1 dependent mechanism, and blunts B cell activation. Thus, our findings suggest Gal-9 intrinsically regulates B cell activation and may differentially modulate BCR signaling at steady state and within germinal centers.

Deciphering Protein O-Glycosylation: Solid-Phase Chemoenzymatic Cleavage and Enrichment.

Abstract: Glycosylation plays a critical role in the biosynthetic-secretory pathway in the endoplasmic reticulum (ER) and Golgi apparatus. Over 50% of mammalian cellular proteins are typically glycosylated; this modification is involved in a wide range of biological functions such as barrier formation against intestinal microbes and serves as signaling molecules for selectins and galectins in the innate immune system. N-linked glycosylation analysis has been greatly facilitated owing to a range of specific enzymes available for their release. However, system-wide analysis on O-linked glycosylation remains a challenge due to the lack of equivalent enzymes and the inherent structural heterogeneity of O-glycans. Although O-glycosidase can catalyze the removal of core 1 and core 3 O-linked disaccharides from glycoproteins, analysis of other types of O-glycans remains difficult, particularly when residing on glycopeptides. Here, we describe a novel chemoenzymatic approach driven by a newly available O-protease and solid...

Exploring functional pairing between surface glycoconjugates and human galectins using programmable glycodendrimersomes.

Abstract: Precise translation of glycan-encoded information into cellular activity depends critically on highly specific functional pairing between glycans and their human lectin counter receptors Sulfoglycolipids, such as sulfatides, are important glycolipid components of the biological membranes found in the nervous and immune systems The optimal molecular and spatial design aspects of sulfated and nonsulfated glycans with high specificity for lectin-mediated bridging are unknown To elucidate how different molecular and spatial aspects combine to ensure the high specificity of lectin-mediated bridging, a bottom-up toolbox is devised To this end, negatively surface-charged glycodendrimersomes (GDSs), of different nanoscale dimensions, containing sulfo-lactose groups are self-assembled in buffer from a synthetic sulfatide mimic: Janus glycodendrimer (JGD) containing a 3'-O-sulfo-lactose headgroup Also prepared for comparative analysis are GDSs with nonsulfated lactose, a common epitope of human membranes These self-assembled GDSs are employed in aggregation assays with 15 galectins, comprising disease-related human galectins, and other natural and engineered variants from four families, having homodimeric, heterodimeric, and chimera architectures There are pronounced differences in aggregation capacity between human homodimeric and heterodimeric galectins, and also with respect to their responsiveness to the charge of carbohydrate-derived ligand Assays reveal strong differential impact of ligand surface charge and density, as well as lectin concentration and structure, on the extent of surface cross-linking These findings demonstrate how synthetic JGD-headgroup tailoring teamed with protein engineering and network assays can help explain how molecular matchmaking operates in the cellular context of glycan and lectin complexity

The Role of Collectins and Galectins in Lung Innate Immune Defense.

Abstract: Different families of endogenous lectins use complementary defense strategies against pathogens. They may recognize non-self glycans typically found on pathogens and/or host glycans. The collectin and galectin families are prominent examples of these two lectin categories. Collectins are C-type lectins that contain a carbohydrate recognition domain and a collagen-like domain. Members of this group include surfactant protein A (SP-A) and D (SP-D), secreted by the alveolar epithelium to the alveolar fluid. Lung collectins bind to several microorganisms, which results in pathogen aggregation and/or killing, and enhances phagocytosis of pathogens by alveolar macrophages. Moreover, SP-A and SP-D influence macrophage responses, contributing to resolution of inflammation, and SP-A is essential for tissue-repair functions of macrophages. Galectins also function by interacting directly with pathogens or by modulating the immune system in response to the infection. Direct binding may result in enhanced or impaired infection of target cells, or can have microbicidal effects. Immunomodulatory effects of galectins include recruitment of immune cells to the site of infection, promotion of neutrophil function, and stimulation of the bactericidal activity of infected macrophages. Moreover, intracellular galectins can serve as danger receptors, promoting autophagy of the invading pathogen. This review will focus on the role of collectins and galectins in pathogen clearance and immune response activation in infectious diseases of the respiratory system.

Different angioregulatory activity of monovalent galectin-9 isoforms.

Abstract: Galectin-9 consists of two peptide-linked carbohydrate recognition domains (CRDs), but alternative splicing and proteolytic processing can give rise to multiple galectin-9 isoforms. Some of these consist of a single CRD and can exert different functions in cell biology. Here, we explored the role of these galectin-9 isoforms in endothelial cell function and angiogenesis. For this, we compared the effects of the two separate CRDs (Gal-9N and Gal-9C) with the tandem repeat galectin-9M on endothelial cell proliferation, migration, sprouting and tube formation in vitro as well as on angiogenesis in vivo using the chicken chorioallantoic membrane (CAM) assay. Galectin-9 isoforms significantly affected proliferation in quiescent endothelial cells and migration in activated endothelial cells. Interestingly, both monovalent gal-9 CRDs displayed opposite effects compared to gal-9M on proliferation and migration. Sprouting was significantly inhibited by gal-9C, while all isoforms appeared to stimulate tube formation. Angiogenesis in vivo was hampered by all three isoforms with predominant effects on vessel length. In general, the isoforms induced only subtle concentration-dependent effects in vitro as well as in vivo. Collectively, the effects of different galectin-9 isoforms in endothelial cell biology depend on the cellular activation status. While opposing effects can be observed on a cellular level in vitro, all galectin-9 isoforms hamper angiogenesis in vivo. This warrants further investigation of the regulatory mechanisms that underlie the diverging roles of galectin-9 isoforms in endothelial cell biology since this could provide therapeutic opportunities.

Regulation of TNF-Related Apoptosis-Inducing Ligand Signaling by Glycosylation.

Abstract: Tumor necrosis-factor related apoptosis-inducing ligand, also known as TRAIL or APO2L (Apo-2 ligand), is a cytokine of the TNF superfamily acknowledged for its ability to trigger selective apoptosis in tumor cells while being relatively safe towards normal cells. Its binding to its cognate agonist receptors, namely death receptor 4 (DR4) and/or DR5, can induce the formation of a membrane-bound macromolecular complex, coined DISC (death-signaling inducing complex), necessary and sufficient to engage the apoptotic machinery. At the very proximal level, TRAIL DISC formation and activation of apoptosis is regulated both by antagonist receptors and by glycosylation. Remarkably, though, despite the fact that all membrane-bound TRAIL receptors harbor putative glycosylation sites, only pro-apoptotic signaling through DR4 and DR5 has, so far, been found to be regulated by N- and O-glycosylation, respectively. Because putative N-glycosylation sequons and O-glycosylation sites are also found and conserved in all these receptors throughout all animal species (in which these receptors have been identified), glycosylation is likely to play a more prominent role than anticipated in regulating receptor/receptor interactions or trafficking, ultimately defining cell fate through TRAIL stimulation. This review aims to present and discuss these emerging concepts, the comprehension of which is likely to lead to innovative anticancer therapies.

Galectin-9 binds IgM-BCR to regulate B cell signaling

Abstract: The galectin family of secreted lectins have emerged as important regulators of immune cell function; however, their role in B-cell responses is poorly understood. Here we identify IgM-BCR as a ligand for galectin-9. Furthermore, we show enhanced BCR microcluster formation and signaling in galectin-9-deficient B cells. Notably, treatment with exogenous recombinant galectin-9 nearly completely abolishes BCR signaling. We investigated the molecular mechanism for galectin-9-mediated inhibition of BCR signaling using super-resolution imaging and single-particle tracking. We show that galectin-9 merges pre-existing nanoclusters of IgM-BCR, immobilizes IgM-BCR, and relocalizes IgM-BCR together with the inhibitory molecules CD45 and CD22. In resting naive cells, we use dual-color super-resolution imaging to demonstrate that galectin-9 mediates the close association of IgM and CD22, and propose that the loss of this association provides a mechanism for enhanced activation of galectin-9-deficient B cells. The galectin family of secreted lectins are important regulators of immune cell function; however, their role in B cell responses is poorly understood. Here, the authors identify IgM-BCR as a ligand for galectin-9. In resting naive cells, they show that galectin-9 mediates a close association between IgM and CD22.

EZH2 promotes hepatocellular carcinoma progression through modulating miR-22/galectin-9 axis

Abstract: Recent studies have shown that interferon-γ (IFN-γ)-induced galectin-9 expression in Kupffer cells plays an essential role in modulatingthe microenvironment of hepatitis-associated hepatocellular carcinoma (HCC). However, whether or not IFN-γ induces galectin-9 expression in HCC cells, its biological role and regulatory mechanism in HCC development and progression are poorly defined. Quantitative PCR and western blotting analysis were used to detect galectin-9 and EZH2 levels in HCC cell lines stimulated with IFN-γ. Bioinformatics analysis and luciferase reporter assay were utilized to confirmthe binding ofmiR-22 to the 3′ untranslated region (3’-UTR) of galectin-9. The methylation status of miR-22 promoter was analyzed by MSP (Methylation specific PCR) and BSP (bisulfite sequencing PCR), while chromatin immunoprecipitation (ChIP) assay identify the occupation status of EZH2 and H3K27me3 at the promoter. Furthermore, the effect of ectopic expression of galectin-9 and miR-22 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK-8, transwell assays and flow cytometric analysis, respectively. IFN-γ induces up-regulation of galectin-9 and EZH2 in HCC cell lines. Galectin-9 is a target of miR-22 and EZH2 facilitates galectin-9 expression by tri-methylation of H3K27 on miR-22 promoter but not hyper-methylation status of DNA. MiR-22 overexpression suppressed HCC cell growth, invasion, and metastasis both in vitro and in vivo. Interestingly, galectin-9 also exhibited antitumor effects, and restoring galectin-9 expression in miR-22 overexpressing cells strengthened its antitumor effects. These findings indicated that EZH2 facilitates galectin-9 expression by epigenetically repressing miR-22 and that galectin-9, which is known as an immunosuppressant, also functions as a tumor suppressor in HCC.

Dissecting the Structure-Activity Relationship of Galectin-Ligand Interactions.

Abstract: Galectins are β-galactoside-binding proteins. As carbohydrate-binding proteins, they participate in intracellular trafficking, cell adhesion, and cell–cell signaling. Accumulating evidence indicates that they play a pivotal role in numerous physiological and pathological activities, such as the regulation on cancer progression, inflammation, immune response, and bacterial and viral infections. Galectins have drawn much attention as targets for therapeutic interventions. Several molecules have been developed as galectin inhibitors. In particular, TD139, a thiodigalactoside derivative, is currently examined in clinical trials for the treatment of idiopathic pulmonary fibrosis. Herein, we provide an in-depth review on the development of galectin inhibitors, aiming at the dissection of the structure–activity relationship to demonstrate how inhibitors interact with galectin(s). We especially integrate the structural information established by X-ray crystallography with several biophysical methods to offer, not only in-depth understanding at the molecular level, but also insights to tackle the existing challenges.

Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models

Abstract: Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

Molecular characterization of Trichinella spiralis galectin and its participation in larval invasion of host’s intestinal epithelial cells

Abstract: The aim of this study was to study the molecular characteristics of Trichinella spiralis galectin (Tsgal) and interactions between Tsgal and host’s intestinal epithelial cells (IECs). The functional domain of Tsgal was cloned and expressed in an E. coli system. The Tsgal was 97.1% identity to the galectin of T. nativa and 20.8% identity to the galectin-8 of humans. Conserved domain analysis revealed that Tsgal belongs to TR-type galectin and has two carbon recognized domain. The rTsgal with 29.1 kDa could be recognized by T. spiralis-infected mice at 42 days post-infection (dpi). The transcription and expression of Tsgal gene was detected by RT-PCR and Western blotting in all T. spiralis developmental stages (intestinal infective larvae, adult worms, newborn larvae, and muscle larvae). The IFA results revealed that Tsgal was mainly located at the cuticles and stichosomes of T. spiralis larvae (ML, IIL and NBL). The rTsgal had hemagglutinating function for erythrocytes from human, rabbit and mouse. The results of Far Western blot and confocal microscopy indicated there was specific binding between rTsgal and IECs, and the binding was located the membrane and cytoplasm of the IECs. Out of four sugars (sucrose, glucose, lactose and maltose), only lactose was able to inhibit the rTsgal agglutinating role for human type B erythrocytes. Moreover, the rTsgal could promote the larval invasion of IECs, while the anti-rTsgal serum inhibited the larval invasion. These results demonstrated that Tsgal might participate in the T. spiralis invasion of intestinal epithelium in early infection stage.

Galectin-8 induces functional disease markers in human osteoarthritis and cooperates with galectins-1 and -3.

Abstract: The reading of glycan-encoded signals by tissue lectins is considered a major route of the flow of biological information in many (patho)physiological processes. The arising challenge for current research is to proceed from work on a distinct protein to family-wide testing of lectin function. Having previously identified homodimeric galectin-1 and chimera-type galectin-3 as molecular switches in osteoarthritis progression, we here provide proof-of-principle evidence for an intra-network cooperation of galectins with three types of modular architecture. We show that the presence of tandem-repeat-type galectin-8 significantly correlated with cartilage degeneration and that it is secreted by osteoarthritic chondrocytes. Glycan-inhibitable surface binding of galectin-8 to these cells increased gene transcription and the secretion of functional disease markers. The natural variant galectin-8 (F19Y) was less active than the prevalent form. Genome-wide array analysis revealed induction of a pro-degradative/inflammatory gene signature, largely under control of NF-κB signaling. This signature overlapped with respective gene-expression patterns elicited by galectins-1 and -3, but also presented supplementary features. Functional assays with mixtures of galectins that mimic the pathophysiological status unveiled cooperation between the three galectins. Our findings shape the novel concept to consider individual galectins as part of a so far not realized teamwork in osteoarthritis pathogenesis, with relevance beyond this disease.

A Brief History of Charcot-Leyden Crystal Protein/Galectin-10 Research.

Abstract: Eosinophils are present in tissues, such as the respiratory tract, spleen, lymph nodes and blood vessels. The significant presence of eosinophils in these tissues are associated with various diseases, including asthma, allergies, acute myeloid leukemia, etc. Charcot-Leyden crystal protein/galectin-10 is overexpressed in eosinophils and has also been identified in basophils and macrophages. In human body, this protein could spontaneously form Charcot-Leyden crystal in lymphocytes or in the lysates of lymphocytes. At present, the role of Charcot-Leyden crystal protein/galectin-10 in lymphocytes is not fully understood. This review summarizes research progress on Charcot-Leyden crystal protein/galectin-10, with emphasis on its history, cellular distributions, relations to diseases, structures and ligand binding specificity.

The Role of Galectins in Cervical Cancer Biology and Progression.

Abstract: Cervical cancer is one of the malignant tumors with high incidence and high mortality among women in developing countries. The main factors affecting the prognosis of cervical cancer are the late recurrence and metastasis and the effective adjuvant treatment, which is radiation and chemotherapy or combination therapy. Galectins, a family containing many carbohydrate binding proteins, are closely involved in the occurrence and development of tumor. They are involved in tumor cells transformation, angiogenesis, metastasis, immune escape, and sensitivity against radiation and chemotherapy. Therefore, galectins are deemed as the targets of multifunctional cancer treatment. In this review, we mainly focus on the role of galectins, especially galectin-1, galectin-3, galectin-7, and galectin-9 in cervical cancer, and provide theoretical basis for potential targeted treatment of cervical cancer.

Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes.

Abstract: While glycans are generally displayed on the cell surface or confined within the lumen of organelles, they can become exposed to the cytosolic milieu upon disruption of organelle membrane by various stresses or pathogens. Galectins are a family of β-galactoside-binding animal lectins synthesized and predominantly localized in the cytosol. Recent research indicates that some galectins may act as "danger signal sensors" by detecting unusual exposure of glycans to the cytosol. Galectin-8 was shown to promote antibacterial autophagy by recognizing host glycans on ruptured vacuolar membranes and interacting with the autophagy adaptor protein NDP52. Galectin-3 also accumulates at damaged phagosomes containing bacteria; however, its functional consequence remains obscure. By studying mouse macrophages infected with Listeria monocytogenes (LM), we showed that endogenous galectin-3 protects intracellular LM by suppressing the autophagic response through a host N-glycan-dependent mechanism. Knock out of the galectin-3 gene resulted in enhanced LC3 recruitment to LM and decreased bacterial replication, a phenotype recapitulated when Galectin-8-deficient macrophages were depleted of N-glycans. Moreover, we explored the concept that alterations in cell surface glycosylation by extracellular factors can be deciphered by cytosolic galectins during the process of phagocytosis/endocytosis, followed by rupture of phagosomal/endosomal membrane. Notably, treatment of cells with sialidase, which removes sialic acid from glycans, resulted in increased galectin-3 accumulation and decreased galectin-8 recruitment at damaged phagosomes, and led to a stronger anti-autophagic response. Our findings demonstrate that cytosolic galectins may sense changes in glycosylation at the cell surface and modulate cellular response through differential recognition of glycans on ruptured phagosomal membranes.