Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness.

Koutsogiannis, Zisis; Mina, John G; Albus, Christin A; Kol, Matthijs A; Holthuis, Joost C M; Pohl, Ehmke; Denny, Paul W

Abstract

Toxoplasma gondii is an obligate, intracellular apicomplexan protozoan parasite of both humans and animals that can cause fetal damage and abortion and severe disease in the immunosuppressed. Sphingolipids have indispensable functions as signaling molecules and are essential and ubiquitous components of eukaryotic membranes that are both synthesized and scavenged by the Apicomplexa. Ceramide is the precursor for all sphingolipids, and here we report the identification, localization and analyses of the Toxoplasma ceramide synthases TgCerS1 and TgCerS2. Interestingly, we observed that while TgCerS1 was a fully functional orthologue of the yeast ceramide synthase (Lag1p) capable of catalyzing the conversion of sphinganine to ceramide, in contrast TgCerS2 was catalytically inactive. Furthermore, genomic deletion of TgCerS1 using CRISPR/Cas-9 led to viable but slow-growing parasites indicating its importance but not indispensability. In contrast, genomic knock out of TgCerS2 was only accessible utilizing the rapamycin-inducible Cre recombinase system. Surprisingly, the results demonstrated that this "pseudo" ceramide synthase, TgCerS2, has a considerably greater role in parasite fitness than its catalytically active orthologue (TgCerS1). Phylogenetic analyses indicated that, as in humans and plants, the ceramide synthase isoforms found in Toxoplasma and other Apicomplexa may have arisen through gene duplication. However, in the Apicomplexa the duplicated copy is hypothesized to have subsequently evolved into a non-functional "pseudo" ceramide synthase. This arrangement is unique to the Apicomplexa and further illustrates the unusual biology that characterize these protozoan parasites. [Abstract copyright: © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.]

Citation

Koutsogiannis, Z., Mina, J. G., Albus, C. A., Kol, M. A., Holthuis, J. C. M., Pohl, E., & Denny, P. W. (2023). Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness. FASEB Journal, 37(11), Article e23229. https://doi.org/10.1096/fj.202201603RRR

• Journal Article Type: Article
• Acceptance Date: Sep 18, 2023
• Online Publication Date: Oct 5, 2023
• Publication Date: 2023-11
• Deposit Date: Oct 23, 2023
• Publicly Available Date: Oct 23, 2023
• Journal: FASEB Journal
• Print ISSN: 0892-6638
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Peer Reviewed: Peer Reviewed
• Volume: 37
• Issue: 11
• Article Number: e23229
• DOI: https://doi.org/10.1096/fj.202201603RRR
• Public URL: https://durham-repository.worktribe.com/output/1807809