Two essential Thioredoxins mediate apicoplast biogenesis, protein import, and gene expression in Toxoplasma gondii

Biddau, M. et al. (2018) Two essential Thioredoxins mediate apicoplast biogenesis, protein import, and gene expression in Toxoplasma gondii. PLoS Pathogens, 14(2), e1006836. (doi:10.1371/journal.ppat.1006836) (PMID:29470517) (PMCID:PMC5823475)

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Abstract

Apicomplexan parasites are global killers, being the causative agents of diseases like toxoplasmosis and malaria. These parasites are known to be hypersensitive to redox imbalance, yet little is understood about the cellular roles of their various redox regulators. The apicoplast, an essential plastid organelle, is a verified apicomplexan drug target. Nuclear-encoded apicoplast proteins traffic through the ER and multiple apicoplast sub-compartments to their place of function. We propose that thioredoxins contribute to the control of protein trafficking and of protein function within these apicoplast compartments. We studied the role of two Toxoplasma gondii apicoplast thioredoxins (TgATrx), both essential for parasite survival. By describing the cellular phenotypes of the conditional depletion of either of these redox regulated enzymes we show that each of them contributes to a different apicoplast biogenesis pathway. We provide evidence for TgATrx1’s involvement in ER to apicoplast trafficking and TgATrx2 in the control of apicoplast gene expression components. Substrate pull-down further recognizes gene expression factors that interact with TgATrx2. We use genetic complementation to demonstrate that the function of both TgATrxs is dependent on their disulphide exchange activity. Finally, TgATrx2 is divergent from human thioredoxins. We demonstrate its activity in vitro thus providing scope for drug screening. Our study represents the first functional characterization of thioredoxins in Toxoplasma, highlights the importance of redox regulation of apicoplast functions and provides new tools to study redox biology in these parasites.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Biddau, Dr Marco and Ovciarikova, Miss Jana and Major, Mr Jack and Sheiner, Dr Lilach and Oka, Dr Ojore
Creator Roles:
Biddau, M.Methodology, Writing – review and editing
Major, J.Methodology
Oka, O.Methodology
Ovciarikova, J.Methodology
Sheiner, L.Conceptualization, Funding acquisition, Methodology, Supervision, Writing – original draft
Authors: Biddau, M., Bouchut, A., Major, J., Saveria, T., Tottey, J., Oka, O., van-Lith, M., Jennings, K. E., Ovciarikova, J., DeRocher, A., Striepen, B., Waller, R. F., Parsons, M., and Sheiner, L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2018 Biddau et al.
First Published:First published in PLoS Pathogens 14(2):e1006836
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
692421Dissection of the unusual mitochondrial tRNA import translocon of Toxoplasma gondiiLilach SheinerBiotechnology and Biological Sciences Research Council (BBSRC)BB/N003675/1III - PARASITOLOGY