The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention?

Abstract

The ubiquitin/proteasome system serves as a regulated protein degradation pathway in eukaryotes, and is involved in many cellular processes featuring high protein turnover rates, such as cell cycle control, stress response and signal transduction. In malaria parasites, protein quality control is potentially important because of the high replication rate and the rapid transformations of the parasite during life cycle progression. The proteasome is the core of the degradation pathway, and is a major proteolytic complex responsible for the degradation and recycling of non-functional ubiquitinated proteins. Annotation of the genome for Plasmodium falciparum, the causative agent of malaria tropica, revealed proteins with similarity to human 26S proteasome subunits. In addition, a bacterial ClpQ/hslV threonine peptidase-like protein was identified. In recent years several independent studies indicated an essential function of the parasite proteasome for the liver, blood and transmission stages. In this review, we compile evidence for protein recycling in Plasmodium parasites and discuss the role of the 26S proteasome as a prospective multi-stage target for antimalarial drug discovery programs.

Keywords: Inhibitor; Plasmodium falciparum; Proteasome; Ubiquitin.

Graphical abstract

Fig. 1

The UPS of eukaryotes. The schematic depicts the structure of the 26S proteasome as well as protein ubiquitination, shuttle and deubiquitination, as experimentally demonstrated in human and yeast. UPS proteins identified in P. falciparum are framed in black, proteins without homologs in P. falciparum are framed in grey. CP, core particle; DUB, deubiquitinating enzyme; E, ubiquitinating enzyme; RA, regulatory activator; RP, regulatory particle; SU, subunit; Ub, ubiquitin.

Fig. 2

(A) Subcellular localization of proteasome SUs and of PfhslV in the blood and gametocyte stages of P. falciparum. Indirect immunofluorescence assays, using mouse polyclonal antisera against α-SU type 5 (A) and β-SU type 5 (B) revealed localization of the two proteins in the asexual blood stages as well as in the gametocyte stages (stages IIb and V depicted). Antibodies antisera against PfhslV (C) labeled the protein in the trophozoite and schizont stages, but not in gametocytes (green). Nuclei were highlighted by Hoechst nuclear staining (blue); and erythrocytes were counterstained by Evans Blue (red). GC, gametocyte; RBC, red blood cell; RS; ring stage, SZ, schizont; TZ, trophozoite. Bar, 5 μm. For detailed methods, see Supplementary data. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Chemical structures of proteasome inhibitors. Functional groups undergoing covalent attachment to the proteasome active centers are highlighted in red. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)