Plasmodium falciparum GCN5 acetyltransferase follows a novel proteolytic processing pathway essential for its function

Abstract

The pathogenesis of human malarial parasite Plasmodium falciparum is interlinked with the timely controlled gene expression during its complex life cycle. Therefore, epigenetic mechanisms are of paramount importance for parasite gene expression. PfGCN5 histone acetyltransferase (HAT), an essential enzyme, acetylates histone 3 and regulates global gene expression in the parasite. Here, we show the existence of a novel proteolytic processing of PfGCN5 that is crucial for its activity in vivo. We find that a cysteine protease like enzyme is required for the processing of PfGCN5 protein. Immunofluorescence and immuno-EM analysis suggest that the processing event occurs around the digestive vacuole of the parasite following the classical ER-Golgi secretory pathway before it reaches nucleus. Furthermore, blocking of PfGCN5 processing leads to the concomitant reduction of protein occupancy at the gene promoters with reduced H3K9 acetylation level, highlighting the important correlation between the processing event and its activity. Altogether, our study reveals a unique processing event of a nuclear protein PfGCN5 with unforeseen role of a food vacuolar cysteine protease with possibility of the development of new antimalarials against these targets.