Toxoplasma gondii establishes a lifelong chronic infection in humans and animals1. Host cell entry and egress are key steps in the lytic cycle of this obligate intracellular parasite, ensuring its survival and dissemination. Egress is temporally orchestrated, underpinned by the exocytosis of secretory organelles called micronemes. At any point during intracellular replication, deleterious environmental changes such as the loss of host cell integrity can trigger egress2 through the activation of the cyclic guanosine monophosphate-dependent protein kinase G3. Notably, even in the absence of extrinsic signals, the parasites egress from infected cells in a coordinated manner after five to six cycles of endodyogeny multiplication. Here we show that diacylglycerol kinase 2 is secreted into the parasitophorous vacuole, where it produces phosphatidic acid. Phosphatidic acid acts as an intrinsic signal that elicits natural egress upstream of an atypical guanylate cyclase (GC), which is uniquely conserved in alveolates4 and ciliates5, and composed of a P4-ATPase and two GC catalytic domains. Assembly of GC at the plasma membrane depends on two associated cofactors — the cell division control 50.1 and a unique GC organizer. This study reveals the existence of a signalling platform that responds to an intrinsic lipid mediator and extrinsic signals to control programmed and induced egress.
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This research was supported by Swiss National Science Foundation (FN3100A0-116722 to D.S.-F. and BSSGI0-155852 to M.B.) and H.B. is the recipient of a Swiss Government Excellence Scholarship with Uruguay. We thank N. Klages, J. B. Marq for their technical contributions to the project; H. Bullen and N. Tosetti for the preliminary investigations on DGKs; D. Sibley and K. Brown for sharing the mAID system prior to publication and for advice; members of the proteomics, bioimaging and flow-cytometry core facilities at the Faculty of Medicine of the University of Geneva; and all meBOP students of 2018 for repeating some of the presented experiments and critically challenging the proposed model.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–3, Supplementary Figures 5 and 6, and Supplementary Table 3.
Alignment of full length UGO orthologue genes. Output of the sequence alignment obtained with MUSCLE was curated manually utilizing BioEdit.
Number of unique spectral counts detected for GC interactors.
Primers used in this study.
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