A new nuclear function of the Entamoeba histolytica glycolytic enzyme enolase: the metabolic regulation of cytosine-5 methyltransferase 2 (Dnmt2) activity

Cytosine-5 methyltransferases of the dnmt2 family function as dna and trna methyltransferases. insight into the role and biological significance of dnmt2 is greatly hampered by a lack of knowledge about its protein interactions. in this report,we address the subject of protein interaction by identifying enolase through a yeast two-hybrid screen as a dnmt2-binding protein. enolase,which is known to catalyze the conversion of 2-phosphoglycerate (2-pg) to phosphoenolpyruvate (pep),was shown to have both a cytoplasmatic and a nuclear localization in the parasite entamoeba histolytica. we discovered that enolase acts as a dnmt2 inhibitor. this unexpected inhibitory activity was antagonized by 2-pg,which suggests that glucose metabolism controls the non-glycolytic function of enolase. interestingly,glucose starvation drives enolase to accumulate within the nucleus,which in turn leads to the formation of additional enolase-e.histolytica dnmt2 homolog (ehmeth) complex,and to a significant reduction of the trnaasp methylation in the parasite. the crucial role of enolase as a dnmt2 inhibitor was also demonstrated in e.histolytica expressing a nuclear localization signal (nls)-fused-enolase. these results establish enolase as the first dnmt2 interacting protein,and highlight an unexpected role of a glycolytic enzyme in the modulation of dnmt2 activity. © 2010 ankri et al.