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

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.