Galectin-3: Integrator of Signaling via Hexosamine Flux

Galectin-3 is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a biomarker for multiple clinically important disorders, including cardiovascular disease. Galectin-3 binds to cell surface glycans to form lattices that modulate surface receptor signaling and internalization. However, the tissue-specific regulation of galectin-3 surface expression remains poorly understood. Here, we review evidence for the involvement of galectin-3 in cell surface signaling, intranuclear events, and intracellular trafficking. Our focus will be on the O-GlcNAc modification as a regulator of galectin-3 biosynthesis, non-canonical secretion, and recycling. We argue that the nutrient-driven cytoplasmic hexosamine biosynthetic pathway (HBP) and endomembrane transport mechanisms generate unique pools of nucleotide sugars. The differing levels of nucleotide sugars in the cytosol, endoplasmic reticulum (ER), and Golgi apparatus generate differential thresholds for responsiveness of O-GlcNAc cycling, N- and O- linked glycan synthesis/branching, and glycolipid synthesis. By regulating galectin-3 synthesis and non-canonical secretion, O-GlcNAc cycling may serve as a nexus constraining galectin-3 cell surface expression and lattice formation. This homeostatic feedback mechanism would be critical under conditions where extensive glycan synthesis and branching in the endomembrane system and cell surface are maintained by elevated hexosamine synthesis. Thus, O-GlcNAc cycling and galectin-3 synergize to regulate galectin-3 secretion and influence cellular signaling. In humans, galectin-3 serves as an early-stage diagnostic biomarker for heart disease, kidney disease, viral infection, autoimmune disease, and neurodegenerative disorders. Since O-GlcNAc cycling has also been linked to these pathologic states, exploring the interconnections between O-GlcNAc cycling and galectin-3 expression and synthesis is likely to emerge as an exciting area of research.