Galectokines: The Promiscuous Relationship between Galectins and Cytokines

Abstract

Galectins, a family of glycan-binding proteins, are well-known for their role in shaping the immune microenvironment. They can directly affect the activity and survival of different immune cell subtypes. Recent evidence suggests that galectins also indirectly affect the immune response by binding to members of another immunoregulatory protein family, i.e., cytokines. Such galectin-cytokine heterodimers, here referred to as galectokines, add a new layer of complexity to the regulation of immune homeostasis. Here, we summarize the current knowledge with regard to galectokine formation and function. We describe the known and potential mechanisms by which galectokines can help to shape the immune microenvironment. Finally, the outstanding questions and challenges for future research regarding the role of galectokines in immunomodulation are discussed.

Keywords: cancer; chemokine; glycobiology; immune response; immunity; protein interaction.

Figure 2

The galectin protein family. (a) Cartoon of the conserved galectin carbohydrate recognition domain based on the crystal structure of galectin-1 (PDB: 3OYW). The CRD consists of two β-sheets that are slightly bent. The convex side consists of 5 antiparallel strands (F1–F5; in yellow) and the concave side of 6 antiparallel strands (S1–S6; in blue). Carbohydrate binding occurs at the concave side and involves several conserved amino acids in S4–S6. The inset shows the organization of the different β-sheets within the amino acid sequence in relation to their location in the convex (F) or concave (S) sheet. (b) Schematic representation of the three galectin subgroups and their respective members based on structural features. While heterodimerization can occur, only homodimers are shown for clarity. (c) Schematic representation of the (extra)cellular location of galectins. In the extracellular environment and cell surface, galectins can interact with glycoconjugates (yellow-lightblue) to facilitate, e.g., cell–ECM and cell–cell interactions. In addition, galectins can mediate interactions between molecules (purple / brown) in the cell membrane. In the cytosol and nucleus, galectins can engage in (mostly) glycan-independent protein/protein interactions involved in, e.g., signaling and mRNA splicing. (Adapted from [58]).

Figure 1

The cytokine protein family. (a) Schematic representation of the cytokine superfamily and the main subfamilies. For each subfamily, the structure of a representative member is shown. IFN-γ (PDB: 1HIG); IL-10 (PDB: 2ILK); IL-2 (PDB: 1M47); CXCL4 (PDB: 1F9Q); TNF-α (PDB: 4TSV). (b) Schematic representation of the different cytokine receptor families with a cartoon of the general domain structure (in different colors for the different families) and some key cytokine ligands below.

Figure 3

Overview of the reciprocal relationships between galectins and cytokines and the functional consequences of galectin-cytokine interactions. (a) Illustration showing the reciprocal expression regulation of galectins and cytokines. (b) Illustration depicting the different interactions between galectins and cytokines that have been reported in the literature. This ranges from homotypic interactions within each family (left panel) to heterotypic interactions between members of a specific family (middle panel) as well as heterotypic interactions between members of both families, i.e., galectokines (right panel). (c) Illustration of the different functional effects of galectokines. (I) Galectins in the extracellular matrix can capture/scavenge cytokines, thereby hampering cytokine-mediated signaling. (II) Galectin-cytokine interactions can affect the direct binding of cytokines to their receptor, thereby affecting the activity of receptor signaling. (III + IV) Galectin-cytokine interactions can hamper the formation of other functional homo- and/or heterodimers, thereby interfering with the activity of these dimers in e.g., receptor dimerization/signaling. (V) Galectin-cytokine interactions can alter glycan-binding of galectins which might trigger translocation of the heterodimer to other receptors or alter interactions of cells with the microenvironment or with other cells.

Figure 3

Overview of the reciprocal relationships between galectins and cytokines and the functional consequences of galectin-cytokine interactions. (a) Illustration showing the reciprocal expression regulation of galectins and cytokines. (b) Illustration depicting the different interactions between galectins and cytokines that have been reported in the literature. This ranges from homotypic interactions within each family (left panel) to heterotypic interactions between members of a specific family (middle panel) as well as heterotypic interactions between members of both families, i.e., galectokines (right panel). (c) Illustration of the different functional effects of galectokines. (I) Galectins in the extracellular matrix can capture/scavenge cytokines, thereby hampering cytokine-mediated signaling. (II) Galectin-cytokine interactions can affect the direct binding of cytokines to their receptor, thereby affecting the activity of receptor signaling. (III + IV) Galectin-cytokine interactions can hamper the formation of other functional homo- and/or heterodimers, thereby interfering with the activity of these dimers in e.g., receptor dimerization/signaling. (V) Galectin-cytokine interactions can alter glycan-binding of galectins which might trigger translocation of the heterodimer to other receptors or alter interactions of cells with the microenvironment or with other cells.