Importance of AMP-activated protein kinase (AMPK) in the regulation of TGF-beta pathway and T regulatory cells differentiation

Abstract

Regulatory T cells (Tregs) play an indispensable role in maintaining immunological tolerance and modulating of chronic inflammatory response. A cytokine TGF-Beta is a crucial mediator in the differentiation of Tregs, once it induces the expression of transcription factor FOXP3, main regulator of genes associated to differentiation of these cells. AMP-Activated Protein Kinase (AMPK) is a sensor of the metabolic state in the cell, and it is activated by the increase of intracellular AMP/ATP ratio. AMPK phosphorylates different proteins that results in the inhibition of anabolic pathways like protein synthesis, while stimulate catabolic pathways such as glycolysis restoring the metabolic equilibrium. Interestingly, AMPK also regulates signaling pathways that are not directly associated with energetic metabolism. In this context, it was demonstrated that in fibroblast, AMPK inhibits the TGF-Beta signaling pathway by phosphorylate proteins of Smads complex, and in that way, to repress the nuclear translocation of complex. In addition, our lab demonstrated recently, that the Hexosamine Biosynthetic Pathway (HBP) was activated by TGF-Beta and play an important role in the differentiation of Tregs induced by this cytokine. It is important to highlight, that the enzyme glutamine: fructose-6-phosphate aminotransferase (GFAT1), enzyme that regulated the flux of HBP from glycolysis, also its phosphorylated and negatively regulated by AMPK. However, the participation of AMPK in the Tregs differentiation it is still not clear. Therefore, this project has as goal to study of AMPK role on the negative control of TGF-Beta pathway and Tregs differentiation. (AU)