Protein Prenylation and Hsp40 in Thermotolerance of Plasmodium falciparum Malaria Parasites.

Emily S Mathews,Andrew J Jezewski,Audrey R Odom John,L David Sibley

doi:10.1128/mbio.00760-21

Abstract

ABSTRACTDuring its complex life cycle, the malaria parasite survives dramatic environmental stresses, including large temperature shifts. Protein prenylation is required during asexual replication of Plasmodium falciparum, and the canonical heat shock protein 40 protein (HSP40; PF3D7_1437900) is posttranslationally modified with a 15-carbon farnesyl isoprenyl group. In other organisms, farnesylation of Hsp40 orthologs controls their localization and function in resisting environmental stress. In this work, we find that plastidial isopentenyl pyrophosphate (IPP) synthesis and protein farnesylation are required for malaria parasite survival after cold and heat shock. Furthermore, loss of HSP40 farnesylation alters its membrane attachment and interaction with proteins in essential pathways in the parasite. Together, this work reveals that farnesylation is essential for parasite survival during temperature stress. Farnesylation of HSP40 may promote thermotolerance by guiding distinct chaperone-client protein interactions.

Highlights

During its complex life cycle, the malaria parasite survives dramatic environmental stresses, including large temperature shifts
Because P. falciparum expresses a farnesylated heat shock protein, heat shock protein 40 protein (HSP40), we hypothesized that production of isoprenoids and protein prenylation are required for growth during temperature stress
We reveal that survival during heat or cold shock in P. falciparum requires both de novo isoprenoid biosynthesis and the posttranslational 15-carbon isoprenyl modification called farnesylation

Summary

Introduction

During its complex life cycle, the malaria parasite survives dramatic environmental stresses, including large temperature shifts. P. falciparum assembles isoprenoids de novo through the methylerythritol 4-phosphate (MEP) pathway [18,19,20], localized within the unusual plastidial organelle of the parasite, the apicoplast Chemical inhibition of this pathway by the small molecule fosmidomycin (FSM) is lethal to malaria parasites [18]. FSM-mediated growth inhibition can be rescued by supplementation with isoprenoids such as isopentenyl pyrophosphate (IPP) [21, 22] These studies validate the essentiality of isoprenoid synthesis in asexual P. falciparum, but there have been long-standing questions regarding which biological processes in the parasite require apicoplast isoprenoid biosynthesis. We and others have used chemical labeling to characterize the complete prenylated proteome of intraerythrocytic P. falciparum [30, 31] These studies identify a single heat shock protein 40 (HSP40; PF3D7_1437900) as robustly farnesylated during intraerythrocytic replication

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Conclusion