Regulation of organelle proteostasis by chaperones and Clp interactors in malaria parasites

Malaria is a leading cause of morbidity and mortality worldwide. It is caused by intracellular parasites of the genus Plasmodium but one species in particular, P. falciparum, is responsible for most of the mortality. It is vital that we better understand the fundamental cell biology of this divergent organism, to stay ahead of this deadly disease. P. falciparum contains a unique organelle known as the apicoplast, a distinctive endosymbiont which harbors essential metabolic pathways, and has proven to be an antimalarial drug target. Most of the apicoplast proteins are encoded by the cell nucleus which controls their synthesis. It is unclear how the apicoplast controls its proteostasis, metabolic functions and biogenesis. Previously, we discovered that a Clp (caseinolytic protease) proteolytic system residing within the apicoplast, functions as a key regulator of the organelle’s biology. Our preliminary data support the hypothesis that the plastid uses Clp-mediated degradation as a mechanism to control protein levels and the consequent organellar functions. Using affinity screens, we discovered several key apicoplast proteins that interact with the Clp complex but their biological function is unclear. Here, we used a genetic approach to study the physiological role of three different Clp interactors. We found that an apicoplast-resident Hsp60 homolog termed Cpn60, interacts with the Clp complex, and its knockdown leads to parasite’s death. Additionally, we investigate two other Clp interactors which we termed CAP13 and CAP14. These mechanistic studies shed light on a potential proteostasis network in the organelle and its role in apicoplast biology.