Protein quality control machinery in intracellular protozoan parasites: hopes and challenges for therapeutic targeting

Abstract

Intracellular protozoan parasites have evolved an efficient protein quality control (PQC) network comprising protein folding and degradation machineries that protect the parasite's proteome from environmental perturbations and threats posed by host immune surveillance. Interestingly, the components of PQC machinery in parasites have acquired sequence insertions which may provide additional interaction interfaces and diversify the repertoire of their biological roles. However, the auxiliary functions of PQC machinery remain poorly explored in parasite. A comprehensive understanding of this critical machinery may help to identify robust biological targets for new drugs against acute or latent and drug-resistant infections. Here, we review the dynamic roles of PQC machinery in creating a safe haven for parasite survival in hostile environments, serving as a metabolic sensor to trigger transformation into phenotypically distinct stages, acting as a lynchpin for trafficking of parasite cargo across host membrane for immune evasion and serving as an evolutionary capacitor to buffer mutations and drug-induced proteotoxicity. Versatile roles of PQC machinery open avenues for exploration of new drug targets for anti-parasitic intervention and design of strategies for identification of potential biomarkers for point-of-care diagnosis.

Keywords: Chaperones; HSP; Parasite; Plasmodium, Leishmania, Toxoplasma, Trypanosoma; Protein quality control.

Fig. 1

Comparing the complex digenetic life cycle of representative intracellular parasites (P. falciparum, T. gondii, L. major, and T. cruzi). These parasites encounter frequent environmental fluctuations (temperature, pH, nutrients) and undergo multiple phenotypic transitions during their life cycle. Depending upon environmental factors, the parasite makes critical decisions for proliferation and transmission. Plasmodium spp. and Toxoplasma are spore-forming protists harboring a relict plastid (apicoplast) and apical complex. Leishmania spp. and Trypanosoma spp. are flagellated protists that have unusual kinetoplast-DNA harboring mitochondrion

Fig. 2

Heat map representing the evolutionary divergence of components of protein quality control machinery across various proteomes (across x-axis, left to right). In this heat map, for each query of the P. falciparum protein, a normalized similarity score of respective ortholog in the queried organism is represented in the scale of 0 (white, low similarity) to 1 (blue, high similarity). For instance, HSP70 shows high conservation across proteomes, whereas its co-chaperone HSP40 displays enormous divergence (across proteomes, x-axis) (data is taken from Bhartiya et al. 2015)

Fig. 3

Schematic representation of canonical and potential non-canonical roles of PQC machinery in Plasmodium falciparum (during asexual cycle in RBC). The canonical roles include maintenance of cytosolic and organellar protein homeostasis by coordinating efficient folding/assembly of nascent proteins and elimination of misfolded proteins, while the putative non-canonical roles include maintenance of nuclear and organellar genome dynamics, modulation of epigenetic machinery, organellar biogenesis, metabolic processes, buffering of drug-induced proteotoxicity, and export of critical proteins for parasite survival via classical and non-classical secretory mechanisms. These secretory processes may allow the secretion of stress-related enzymes, HSPs, and virulence factors into the parasitophorous vacuole (PV). The PTEX machinery in the PV exports parasite proteins containing PEXEL or distinct targeting signals in an unfolded state into the host cytosol. The exported protein is refolded by the host HSPs (h-HSPs) and/or exported parasite HSPs (p-HSPs). In the host cytosol, the parasite generates transient organelles like Maurer’s cleft and J-dots that are involved in trafficking of virulence factors to RBC surface for host cell remodeling. It can be hypothesized that (i) exported parasite-PQC (p-PQC) machinery may cross-talk with the host machineries for their own survival, and (ii) exported parasite cargo can be degraded by the host’s proteasome into peptides which are released along with p-HSPs in extracellular vesicles (EVs). These EVs may modulate the host immune response or influence communication with other infected RBCs for gamete formation