Plasmodium falciparum Molecular Chaperones: Guardians of the Malaria Parasite Proteome and Renovators of the Host Proteome

Abstract

Plasmodium falciparum is a unicellular protozoan parasite and causative agent of the most severe form of malaria in humans. The malaria parasite has had to develop sophisticated mechanisms to preserve its proteome under the changing stressful conditions it confronts, particularly when it invades host erythrocytes. Heat shock proteins, especially those that function as molecular chaperones, play a key role in protein homeostasis (proteostasis) of P. falciparum. Soon after invading erythrocytes, the malaria parasite exports a large number of proteins including chaperones, which are responsible for remodeling the infected erythrocyte to enable its survival and pathogenesis. The infected host cell has parasite-resident and erythrocyte-resident chaperones, which appear to play a vital role in the folding and functioning of P. falciparum proteins and potentially host proteins. This review critiques the current understanding of how the major chaperones, particularly the Hsp70 and Hsp40 (or J domain proteins, JDPs) families, contribute to proteostasis of the malaria parasite-infected erythrocytes.

Plasmodium falciparum J‐dot localized J domain protein A8iJp modulates the chaperone activity of human HSPA8

“…Parasite protein export through the parasitophorous vacuolar membrane into the host erythrocyte occurs in an unfolded state, necessitating the assistance of chaperones to maintain their translocation competence and aid in folding [11,12]. Only one PfHSP70 chaperone is exported [17], but it is not vital for parasite growth [22], leading researchers to believe that the parasite may utilize the host HSP70 chaperone for protein folding and host erythrocyte remodeling [23].…”

“…Later, PfHSP70xa PEXEL-negative exported protein, got localized to the J-dots [16,17] and was reported to act as the cognate chaperone for two PfJDPs (PFE0055c and PFA0660w) [18][19][20][21]. Still, the dispensability of PfHSP70x protein [22] for the intraerythrocytic parasite survival made researchers speculate that few of the exported PfJDPs hijack the human erythrocyte HSP70 chaperone function for parasite protein folding [11,23,24]. Recently, a type-IV JDP -PfeCiJp, has been reported as a co-chaperone for the human HsHSPA1 [25].…”

“…To traffic into the host erythrocyte, proteins must unfold and pass through the Protein Translocon complex (PTEX) [9] across the parasitophorous vacuolar membrane. Once translocated into the host erythrocyte, chaperones play a crucial role in maintaining the unfolded parasite protein's translocation competence to sort them into compartments and ensure they are folded into a functional state [10,11].…”

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

“…There is substantial evidence that PfHSPs are not only genuine drug targets but that they also carry highly druggable structural features for antimalarial drug discovery. 9 , 10 , 11 HSPs were discovered on the basis that their expression was significantly upregulated in response to physical, chemical, or physiological stress factors, and they were named according to their apparent molecular weight; for example, HSP70 (HSP70) is a 70 kDa protein. The major families of HSPs (HSP10, HSP40, HSP60, HSP70, HSP90, and HSP100) have now been shown to play essential roles in cell survival not only under stressful conditions but also under normal physiology, with many of them demonstrated to be molecular chaperones with both inducible and constitutive isoforms.…”

“… 16 , 17 Many PfHSPs are also essential for the parasite’s pathogenesis and virulence, and a number form unique complexes at the host–parasite interface. 11 Furthermore, unlike many other antimalarial drug targets studied to date, modulation of PfHSPs could have much broader effects on the survival of the parasite across all stages of the life cycle.…”