Intracellular Galectin-3 Is a Sensor of Lipopolysaccharide that Promotes Glycolysis through Activating mTORC1

Galectin-3 is a carbohydrate binding protein implicated in cell-cell interaction and cell growth. Interestingly, recent studies suggest that galectin-3 is involved in cell metabolism and linked to diabetes and cancer. How galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 is physically associated with Rag GTPases and Ragulator of the mTORC1 signaling machinery on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to activation of Rag GTPases thus lysosomal loading of mTOR and activation of mTORC1. Integrative genomics and transcriptomics analyses reveal that the LPS/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1 (glucose transporter member 1) that functions in glucose uptake and glycolysis and HK2 (hexokinase 2) and PKM2 (pyruvate kinase M2) that catalyze the first and last step of glycolysis, respectively. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, in diabetes patients, the expression of HK2 was significantly reduced, and in hepatocellular carcinoma (HCC), thyroid cancer, and prostate cancer, galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism, adding to the understanding of diabetogenesis and tumorigenesis. Comparative gene expression profiling analysis of RNA-seq data for HEK-293T cells treated with siCon and siGal3 or Control and Torin1. HEK-293T cells were treated with or without siGal3 or Torin 1 for 24 hours, and total RNAs were extracted for cDNA synthesis, library construction and sequencing.