Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Abstract

Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.

Keywords: Plasmodium; acetylation; glutathionylation; glycosylation; lipidation; lipoxidation; methylation; mosquito Anopheles; phosphorylation; ubiquitination.

Figure 1

The life stages of the malaria parasite Plasmodium within both the host and the vector, along with protein post-translational modifications (PTMs) that accompany the parasite life cycle. The parasite stages include sporozoites (s), liver exoerythrocytic forms (EEFs), merozoites (m) (after egress from hepatocytes or erythrocytes, with malarial pigment hemozoin (HZ) released from infected erythrocytes), ring forms (r), trophozoites (t), schizonts (sh), gametocytes (g), male (micro-) or female (macro-) gametes (mg and fg, respectively), zygotes (zg), ookinetes (ok), and oocysts (oc). The life stages in the vector (mosquito) are separated by a dotted line from those in the host (human). Protein PTMs are present or implicated in all parasite stages.