Crossing the Vacuolar Rubicon: Structural Insights into Effector Protein Trafficking in Apicomplexan Parasites.

Apicomplexans form a large phylum of parasitic protozoa, including the genera , and , the causative agents of malaria, toxoplasmosis, and cryptosporidiosis, respectively. They cause diseases not only in humans but also in animals, with dramatic consequences in agriculture. Most apicomplexans are vacuole-dwelling and obligate intracellular parasites; as they invade the host cell, they become encased in a parasitophorous vacuole (PV) derived from the host cellular membrane. This creates a parasite-host interface that acts as a protective barrier but also constitutes an obstacle through which the pathogen must import nutrients, eliminate wastes, and eventually break free upon egress. Completion of the parasitic life cycle requires intense remodeling of the infected host cell. Host cell subversion is mediated by a subset of essential effector parasitic proteins and virulence factors actively trafficked across the PV membrane. In the malaria parasite a unique and highly specialized ATP-driven vacuolar secretion system, the translocon of exported proteins (PTEX), transports effector proteins across the vacuolar membrane. Its core is composed of the three essential proteins EXP2, PTEX150, and HSP101, and is supplemented by the two auxiliary proteins TRX2 and PTEX88. Many but not all secreted malarial effector proteins contain a vacuolar trafficking signal or export element (PEXEL) that requires processing by an endoplasmic reticulum protease, plasmepsin V, for proper export. Because vacuolar parasitic protein export is essential to parasite survival and virulence, this pathway is a promising target for the development of novel antimalarial therapeutics. This review summarizes the current state of structural and mechanistic knowledge on the parasitic vacuolar secretion and effector trafficking pathway, describing its most salient features and discussing the existing differences and commonalities with the vacuolar effector translocation machinery recently described in and other apicomplexans of significance to medical and veterinary sciences.