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A Critical Role for Toxoplasma gondii Vacuolar Protein Sorting VPS9 in Secretory Organelle Biogenesis and Host Infection

Abstract : Accurate sorting of proteins to the three types of parasite-specific secretory organelles namely rhoptry, microneme and dense granule in Toxoplasma gondii is crucial for successful host cell invasion by this obligate intracellular parasite. Despite its tiny body architecture and limited trafficking machinery, T. gondii relies heavily on transport of vesicles containing proteins, lipids and important virulence-like factors that are delivered to these secretory organelles. However, our understanding on how trafficking of vesicles operates in the parasite is still limited. Here, we show that the T. gondii vacuolar protein sorting 9 (TgVps9), has guanine nucleotide exchange factor (GEF) activity towards Rab5a and is crucial for sorting of proteins destined to secretory organelles. Our results illuminate features of TgVps9 protein as a key trafficking facilitator that regulates protein maturation, secretory organelle formation and secretion, thereby ensuring a primary role in host infection by T. gondii. Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a usually mild disease in immunocompetent humans that can turn into a major threat in immunocompromised patients and during primary infection of pregnant woman. T. gondii is a member of the Apicomplexa, a phylum of numerous medically important parasites causing life-threatening diseases in human and animals worldwide. The phylum is typified by specific secretory organelles called rhoptries, micronemes and dense granules that are essential for host cell invasion and host pathway modulation. In Toxoplasma, rhoptries contain two groups, termed rhoptry (ROP) and rhoptry neck (RON), of effector proteins some of which are virulence factors; whereas micronemes secrete MIC proteins that are involved in parasite gliding, host cell attachment and invasion 1,2. After invasion, dense granules discharge GRA proteins involved in parasitophorous vacuole (PV) formation and in hijacking host cell gene expression and metabolism 3. Despite having a single cell architecture, the parasite relies on active and abundant vesicle and protein trafficking. T. gondii and likely all Apicomplexa have reutilized classical endosomal and endocytic trafficking pathways more typical of higher eukaryotes towards building specialized secretory organelles that release parasite effectors to interplay with host cell signaling pathways as a way to take control over host immunity and ultimately to promote long-term parasitism 4–8. It is now well established that apicomplexan parasites operate an unconventional endosome-like system (ELC) to traffic proteins from the Golgi apparatus to rhoptries and micronemes 6–8. However, the mechanisms involved in endosome-like vesicle formation and delivery to the aforementioned organelles in general remain elusive. In mammalian cells, the endosomal system is used for the uptake of plasma membrane-associated components, which after passage through Rab5-positive early endosomes (EE) enter either Rab11A-positive recycling endosomes to return to the plasma membrane, or Rab7-positive late endosomes to be delivered to lysosomes (LE) 9 .
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Takaya Sakura, Fabien Sindikubwabo, Lena Oesterlin, Hugo Bousquet, Christian Slomianny, et al.. A Critical Role for Toxoplasma gondii Vacuolar Protein Sorting VPS9 in Secretory Organelle Biogenesis and Host Infection. Scientific Reports, Nature Publishing Group, 2016, 6, pp.38842. ⟨10.1038/srep38842⟩. ⟨inserm-01472213⟩

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