The Role of Malaria Parasite Heat Shock Proteins in Protein Trafficking and Remodelling of Red Blood Cells

Jonsdottir, Thorey K; Gabriela, Mikha; Gilson, Paul R.

doi:10.1007/978-3-030-78397-6_6

Cited by 4 publications

(4 citation statements)

References 145 publications

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“…While HsJDPs were not detected with as great an intensity as HsHOP, HsHsp70 and HsHsp90, members of all of the different HsJDP classes were identified as significantly enriched: DNAJA2 (DNJ3/mDJ3/Dnaj3/HIRIP4); DNAJA4 (HSJ4/Dj4); DNAJB1 (HSPF1/HSP40); DNAJB2 (HSJ1/HSPF3/Dnajb10/MDJ8); DNAJB4 (Hsc40); DNAJC9 (AU020082/RcDNAJ9); and DNAJC13 (Rme8/RME-8/Gm1124) ( Supplementary Table S2 ; Siddiqui et al, 2022 ). While there is biochemical evidence that full length and functional HsHOP, HsHsp70 and HsHsp90 are present in the infected erythrocyte cytosol ( Banumathy et al, 2002 ; Alampalli et al, 2018 ; Jonsdottir et al, 2021 ), there does not appear to be any such evidence for HsJDPs. The degree of enrichment of the HsJDPs detected by these various proteomics studies, suggests that they are functionally active; but this needs to be experimentally validated.…”

Section: Human Molecular Chaperones Are Enriched In the Infected Eryt...mentioning

confidence: 96%

“…Hence, a key phase in the pathology of malaria is the invasion of erythrocytes by the parasite ( Figure 1 ). This intracellular parasite completely remodels the host cell by exporting around 450 parasite proteins, with heat shock proteins being a major component (∼5%) of the exportome ( Jonsdottir et al, 2021 ). These heat shock proteins appear to play an important role in rebooting the protein folding capacity of the barren erythrocytic compartment, by establishing new co-chaperone-chaperone pathways involving both parasite and host protein machinery.…”

Section: Introductionmentioning

confidence: 99%

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The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery

Almaazmi

Kaur

Singh

et al. 2023

Front. Mol. Biosci.

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Cellular proteostasis requires a network of molecular chaperones and co-chaperones, which facilitate the correct folding and assembly of other proteins, or the degradation of proteins misfolded beyond repair. The function of the major chaperones, heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90), is regulated by a cohort of co-chaperone proteins. The J domain protein (JDP) family is one of the most diverse co-chaperone families, playing an important role in functionalizing the Hsp70 chaperone system to form a powerful protein quality control network. The intracellular malaria parasite, Plasmodium falciparum, has evolved the capacity to invade and reboot mature human erythrocytes, turning them into a vehicles of pathology. This process appears to involve the harnessing of both the human and parasite chaperone machineries. It is well known that malaria parasite-infected erythrocytes are highly enriched in functional human Hsp70 (HsHsp70) and Hsp90 (HsHsp90), while recent proteomics studies have provided evidence that human JDPs (HsJDPs) may also be enriched, but at lower levels. Interestingly, P. falciparum JDPs (PfJDPs) are the most prominent and diverse family of proteins exported into the infected erythrocyte cytosol. We hypothesize that the exported PfJPDs may be an evolutionary consequence of the need to boost chaperone power for specific protein folding pathways that enable both survival and pathogenesis of the malaria parasite. The evidence suggests that there is an intricate network of PfJDP interactions with the exported malarial Hsp70 (PfHsp70-x) and HsHsp70, which appear to be important for the trafficking of key malarial virulence factors, and the proteostasis of protein complexes of human and parasite proteins associated with pathology. This review will critically evaluate the current understanding of the role of exported PfJDPs in pathological exploitation of the proteostasis machinery by fine-tuning the chaperone properties of both human and malarial Hsp70s.

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Section: Human Molecular Chaperones Are Enriched In the Infected Eryt...mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery

Almaazmi

Kaur

Singh

et al. 2023

Front. Mol. Biosci.

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“…Interestingly, there is compelling evidence to suggest that it is imperative to more deeply explore the HSP complexes at the host–parasite interface. 11 , 63 , 100 Comprehensive studies conducted over 20 years ago have already established that full-length and functional human HSP70/HSP90 organizing protein (HOP), HSP70 and HSP90 were present in the infected erythrocyte cytosol, potentially as both the free form and together in a highly complexed state. 101 These findings have been validated by more recent proteomics analyses of knob-associated protein complexes.…”

Section: Hsp Complexes At the Host–parasite Interface Are Also Drug T...mentioning

confidence: 99%

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

Ahmad,

Alhammadi,

Almaazmi

et al. 2024

Cell Stress and Chaperones

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“…The malaria parasite, Plasmodium falciparum , invades the cells of its human host, enabling it to evade the immune system and ultimately harness the cellular machinery to propagate itself and cause severe pathology. Surrounded by a self-created parasitophorous vacuole (PV) within human erythrocytes, the malaria parasite renovates the host cell by exporting over 400 parasite proteins, including a number of heat shock proteins, which oversee protein folding as molecular chaperones and co-chaperones ( Hiller et al, 2004 ; Marti et al, 2004 ; Jonsdottir et al, 2021 ). An important co-chaperone family, the P. falciparum J domain proteins (PfJDPs; also called heat shock protein 40 s, Hsp40s), are localized to almost every compartment of the infected erythrocyte, with arguably the greatest number of exported members of any protein family ( Sargeant et al, 2006 ; Botha et al, 2007 ; Dutta et al, 2021a ; Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Exported J domain proteins of the human malaria parasite

Almaazmi

Singh

Dutta

et al. 2022

Front. Mol. Biosci.

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The heat shock protein 40 (Hsp40) family, also called J domain proteins (JDPs), regulate their Hsp70 partners by ensuring that they are engaging the right substrate at the right time and in the right location within the cell. A number of JDPs can serve as co-chaperone for a particular Hsp70, and so one generally finds many more JDPs than Hsp70s in the cell. In humans there are 13 Hsp70s and 49 JDPs. The human malaria parasite, Plasmodium falciparum, has dedicated an unusually large proportion of its genome to molecular chaperones, with a disproportionately high number of JDPs (PfJDPs) of 49 members. Interestingly, just under half of the PfJDPs are exported into the host cell during the asexual stage of the life cycle, when the malaria parasite invades mature red blood cells. Recent evidence suggests that these PfJDPs may be functionalizing both host and parasite Hsp70s within the infected red blood cell, and thereby driving the renovation of the host cell towards pathological ends. PfJDPs have been found to localize to the host cytosol, mobile structures within the host cytosol (so called “J Dots”), the host plasma membrane, and specialized structures associated with malaria pathology such as the knobs. A number of these exported PfJDPs are essential, and there is growing experimental evidence that they are important for the survival and pathogenesis of the malaria parasite. This review critiques our understanding of the important role these exported PfJDPs play at the host-parasite interface.

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The Role of Malaria Parasite Heat Shock Proteins in Protein Trafficking and Remodelling of Red Blood Cells

Cited by 4 publications

References 145 publications

The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery

The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery

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

Exported J domain proteins of the human malaria parasite

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