Plasmodium falciparum acetyltransferase GCN5 acts as a dual regulator of essential glycolytic enzyme phosphoglycerate mutase.

Abstract

Lysine acetylation is emerging as a key player in cellular regulation across species by controlling the fate of metabolic proteins as well as modulating gene expression via histone modification. Phosphoglycerate mutase, a conserved enzyme of the sole energy-yielding pathway of glycolysis in the human malaria parasite Plasmodium falciparum, is indispensable for its growth. Here, we demonstrate that P. falciparum phosphoglycerate mutase PfPGM1 (phosphoglycerate mutase) is regulated via lysine acetylation. In mammalian cells, acetylation of phosphoglycerate mutase modulates its catalytic activity, although the acetyl transferase enzyme remains elusive. However, the parasites exhibit a unique way of regulating the fate of PfPGM1 via acetylation that modulates its stability, thus providing an increased protein pool for the rapid growth and proliferation of the parasites. We show that K100, a critical residue for PfPGM1 catalytic activity, is acetylated by the essential histone acetyltransferase PfGCN5. Downregulation of PfGCN5 through a knockdown approach in the parasites along with cycloheximide treatment indeed leads to a reduction of PfPGM1 protein. Additionally, PfGCN5 occupies the promoter of PfPGM1 in a stage-specific manner, and downregulation of PfGCN5 protein leads to a reduced transcript level of PfPGM1. Collectively, our data highlight a dual regulation of PfPGM1 by PfGCN5 through acetylation of the protein as well as regulation of the transcription of the gene. Such dual control is not only rare but showcases the importance of the above two proteins and their potential as excellent targets against malaria.