Essential role for HSP40 in asexual replication and thermotolerance of malaria parasites
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Plasmodium falciparum, the parasite responsible for nearly all cases of severe malaria, must survive challenging environments to persist in its human host. Symptomatic malaria is characterized by periodic fevers corresponding to the 48-hour asexual reproduction of P. falciparum in red blood cells. As a result, P. falciparum has evolved a diverse collection of heat shock proteins to mitigate the stresses induced by temperature shifts. Among the assortment of heat shock proteins in P. falciparum , there is only one predicted canonical cytosolic J domain protein, HSP40 (PF3D7_1437900). Here, we generate a HSP40 tunable knockdown strain of P. falciparum to investigate the biological function of HSP40 during the intraerythrocytic lifecycle. We determine that HSP40 is required for malaria parasite asexual replication and survival of febrile temperatures. Previous reports have connected proteotoxic and thermal stress responses in malaria parasites. However, we find HSP40 has a specific role in heat shock survival and does not mitigate the proteotoxic stresses induced by artemisinin or proteosome inhibition. Following HSP40 knockdown, malaria parasites have a cell cycle progression defect and reduced nuclear replication. Untargeted proteomics reveal HSP40 depletion leads to a multifaceted downregulation of DNA replication and repair pathways. Additionally, we find HSP40 knockdown sensitizes parasites to DNA replication inhibition. Overall, these studies define the specialized role of the J domain protein HSP40 in malaria parasites during the blood stages of infection.
Author Summary
Malaria parasites have evolved to survive and cause disease in humans even when they are challenged by the temperature shifts of fever. We are interested in uncovering how malaria parasites persist despite exposure to febrile temperatures. We know the parasite has a diverse collection of heat shock proteins that are important for proper folding of many proteins within cells during stress conditions. In this study, we define the role of one specific heat shock protein, HSP40, by generating a strain of the human malaria parasite P. falciparum where we control the expression of HSP40 during the red blood cell stages of infection. We find that HSP40 is required for malaria parasites to replicate in red blood cells. We demonstrate HSP40 expression to be vital for malaria parasite survival of febrile temperature stress. Additionally, we determine that without HSP40, DNA replication and repair is disrupted. Our work has uncovered essential parasite biology that may be exploited for the development of new antimalarials.
