LGALS9
Description
The LGALS9 (galectin 9) is a protein-coding gene located on chromosome 17.
Galectin-9 was first isolated from mouse embryonic kidney in 1997 as a 36 kDa beta-galactoside lectin protein. Human galectin-9 is encoded by the LGALS9 gene. The protein has N- and C- terminal carbohydrate-binding domains connected by a link peptide. Multiple alternatively spliced transcript variants have been found for this gene. Galectin-9 is one of the most studied ligands for HAVCR2 (TIM-3) and is expressed on various tumor cells. However, it can also interact with other proteins (CLEC7A, CD137, CD40). For example, an interaction with CD40 on T-cells inhibits their proliferation and induces cell death. Galectin-9 also has important cytoplasmic, intracellular functions and controls AMPK in response to lysosomal damage that can occur upon exposure to endogenous and exogenous membrane damaging agents such as crystalline silica, cholesterol crystals, microbial toxins, proteopathic aggregates such as tau fibrils and amyloids, and signaling pathways inducing lysosomal permeabilization such as those initiated by TRAIL. Mild lysosomal damage, such as that caused by the anti-diabetes drug metformin may contribute to the therapeutic action of metformin by activating AMPK. The mechanism of how Galectin-9 activates AMPK involves recognition of exposed lysosomal lumenal glycoproteins such as LAMP1, LAMP2, SCRAB2, TMEM192, etc., repulsion of deubiquitinating enzyme USP9X, increased K63 ubiquitination of TAK1 (MAP3K7) kinase, which in turn phopshorylates AMPK and activates it. This signaling cascade directly links Galectin-9 intracellular function with ubiqutin systems. Galectin-9, through its regulation of AMPK, a kinase that negatively regulates mTOR, cooperates with Galectin-8-based effects to inactivate mTOR downstream of the lysosomal damaging agents and conditions.
Galectin-9, also known as Ecalectin and Tumor antigen HOM-HD-21, is a protein that binds galactosides, particularly the Forssman pentasaccharide. It acts as a ligand for HAVCR2/TIM3, triggering the death of T-helper type 1 lymphocytes (Th1) upon binding. Galectin-9 also stimulates bactericidal activity in infected macrophages by activating them and causing IL1B secretion, restricting intracellular bacterial growth. As a ligand for P4HB, it retains P4HB at the surface of Th2 T-helper cells, increasing disulfide reductase activity at the plasma membrane, modifying the membrane's redox state, and enhancing cell migration. Its interaction with CD44 promotes the binding of SMAD3 to the FOXP3 promoter, leading to increased FOXP3 expression and improved stability and suppressive function of induced regulatory T (iTreg) cells. Galectin-9 contributes to mesenchymal stromal cell suppression of T-cell proliferation, expands regulatory T-cells, and induces cytotoxic T-cell apoptosis following viral infection. It activates ERK1/2 phosphorylation, stimulating the production of cytokines (IL-6, IL-8, IL-12) and chemokine (CCL2) in mast and dendritic cells. It also inhibits mast cell degranulation and induces their apoptosis, while promoting dendritic cell maturation and migration. Galectin-9 inhibits natural killer (NK) cell function and can transform their phenotype from peripheral to decidual during pregnancy. Astrocyte-derived Galectin-9 enhances microglial TNF production. This protein may play a role in thymocyte-epithelial interactions within the thymus. It may also facilitate urate flux across cell membranes, acting as an electrogenic transporter involved in renal and gastrointestinal urate excretion. Galectin-9 displays high selectivity for the anion urate and acts as an eosinophil chemoattractant. It inhibits angiogenesis and suppresses IFNG production by natural killer cells. It exists as a monomer.
LGALS9 is also known as HUAT, LGALS9A.
