Galectins: intra and extracellular functions diagnostic and therapeutic targets in many diseases
Galectins were discovered in a quest to find proteins binding cell surface carbohydrates and taking part in cell adhesion, and this is indeed one of the roles of galectins. However, they have many other roles. Galectins bind β-galactose containing glycans typically found at the cell surface and inside vesicles to form cell surface lattices, regulate of glycoprotein traffic and surface exposure of receptor, induction of endocytosis and others, that translate into higher level roles of galectins in immunity, inflammation and cancer. However, surprisingly, it was early discovered that galectins are synthesized as cytosolic proteins, without a signal peptide, and can also have functions in the cytosolic and nuclear compartments, such as interaction with RAS-proteins, ESCRT-complex, centrosomes and roles in transcription and RNA splicing. At the interface between the cytosolic and intravesicular compartments is the now well established carbohydrate-binding dependent rapid accumulation of galectin around disrupted vesicles and coupling of this to autophagy, and also to secretory autophagy. These multiple seemingly unrelated functional effects, suggest roles of galectins in feed back loops regulating membrane turnover and organization or similar with consequent effects in physiology and pathophysiology.
To help study such galectin related phenomena we have developed binding assays to analyze galectin specificity and aggregation on encounter with natural and artificial ligands, and we have also developed potent small molecule galectin inhibitors (nM affinities) that can either be readily taken up by cells or not, permitting examination of galectin intracellular roles separate from extracellular roles. Such galectin inhibitors are also in development as therapeutics in, for example, cancer, eye disease, and inflammatory disease with fibrosis. One has reached phase IIa clinical trial against idiopathic lung fibrosis.
Lund University Sect MIG, Inst. Laboratory Medicine Dept. Clinical Immunology, Lund University Hopsital Sölvegatan 23 22362 Lund Sweden
Hakon Leffler Lund University Sect MIG, Inst. Laboratory Medicine Dept. Clinical Immunology, Lund University Hopsital Sölvegatan 23 22362 Lund Sweden
Chef d'équipe Directeur UMR3666/U1143
Domain 4 - UMR 3666 / U1143 - Chemical Biology of Membranes and Therapeutic Delivery