Phosphatidic acid governs natural egress in Toxoplasma gondii via a guanylate cyclase receptor platform

Abstract

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 ciliates^5, 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.