Evolving mechanistic insights into galectin functions

Abstract

Galectins are an evolutionarily ancient family of glycan-binding proteins (GBPs) and are found in all animals. Although they were discovered over 30 years ago, ideas about their biological functions continue to evolve. Current evidence indicates that galectins, which are the only known GBPs that occur free in the cytoplasm and extracellularly, are involved in a variety of intracellular and extracellular pathways contributing to homeostasis, cellular turnover, cell adhesion, and immunity. Here we review evolving insights into galectin biology from a historical perspective and explore current evidence regarding biological roles of galectins.

Fig. 1

The galectin family of β-galactoside binding proteins. Galectins are classified into three distinct groups based on their quaternary structure: prototypical, chimeric, and tandem repeat. Prototypical: Gal-1, Gal-2, Gal-7, Gal-10, Gal-13, and Gal-14. Chimeric: Gal-3. Tandem repeat: Gal-4, Gal-8, Gal-9, and Gal-12

Fig. 2

Distinct galectin family members possess the capacity to differentially regulate lymphocytes. Some of the earliest studies suggested that galectins appear to possess immunomodulatory activity by directly impacting T cell viability. Subsequent studies suggested that galectin might not only regulate T cell viability but also regulate cytokine secretion and activation. Several galectins might also play a variety of roles in the development, activation and differentiation of B cells. Similar galectin-mediated regulation may play a role in NK and NKT cell activation and viability. Representative galectin-regulated activities are shown. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity

Fig. 3

Galectins differentially regulate monocytes/macrophages and dendritic cells. Different galectin family members appear to possess the ability to directly impact the activity of monocytes/macrophages and dendritic cells with significant implications not only on generalized inflammation but also on the ability of these cells to engage cells involved in adaptive immunity. Several galectins also appear to directly regulate T cell-antigen presenting cell interactions with implications on subsequent T cell activation and differentiation. Representative galectin-regulated activities are shown. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity

Fig. 4

Galectins regulate granulocyte activation and turnover. Galectin family members appear to possess the ability to differentially activate various granulocytes, including neutrophils, eosinophils, and mast cells. In addition, galectins appear to regulate the turnover and chemotaxis of various granulocyte populations. Representative galectin-regulated activities are shown. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity

Fig. 5

Galectins regulate hemostasis, angiogenesis and tissue repair. Various members of the galectin family regulate megakaryocyte activity, hemostasis, angiogenesis, epithelial migration, and general tissue repair following injury. Representative galectin-regulated activities are shown. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity. Plt = platelet, vWF = von Willebrand Factor

Fig. 6

Galectin family members regulate various intracellular processes. While the earliest studies on galectins demonstrated that these proteins recognize extracellular carbohydrate ligands, subsequent studies have demonstrated that galectins possess significant roles in the regulation of a variety of fundamental intracellular activities, both in the cytoplasm and the nucleus. Representative galectin-regulated activities are shown. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity

Fig. 7

Galectin activity is regulated by oxidation and proteolysis. Galectins, first called S-type lectins secondary to the requirement of several galectins for reduced thiols to maintain carbohydrate recognition activity, can form intramolecular and intermolecular disulfide bridges that often result in significant conformational changes that preclude carbohydrate recognition. As monomers appear to be a key intermediate in oxidative inactivation and carbohydrates can drive dimerization, ligand appears to reduce oxidative inactivation by facilitating dimer formation (K_d¹ < K_d²). [hi] = higher concentrations of Gal-1. [low] = lower concentrations of Gal-1. In contrast, several galectins, especially tandem repeat and chimeric galectins, rely on linker peptide bound carbohydrate recognition domains or N-terminal collagen-like domains to facilitate dimerization/oligomerization. Cleavage of intervening peptides that connect oligomerization domains to functional carbohydrate recognition domains can render carbohydrate recognition domains monomeric and therefore incapable of generating molecular lattices typically thought to be required for optimal galectin-mediated signaling

Fig. 8

Galectins recognize a diverse range of pathogens. While the immunoregulatory roles of galectins likely represent some of their most well known functions, the ability of galectins to recognize a diverse range of pathogens may reflect some of their earliest evolutionary activities. Galectin recognition of pathogens can result in opsonization or direct microbial killing. In contrast, pathogens may utilize galectins to facilitate attachment and invasion. Representative galectin-regulated activities are shown. Red arrows indicate an activity that the respective galectin increases, while blue arrows signify galectin-induced decreases in the accompanying activity