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

Takaya Sakura,Fabien Sindikubwabo,Mohamed-Ali Hakimi,Stanislas Tomavo,Christian Slomianny,Lena K Oesterlin,Gordon Langsley,Hugo Bousquet

doi:10.1038/srep38842

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.

Highlights

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
We report that the T. gondii counterpart of Vps[9] is a bona fide Rab[5] guanosine triphosphate (GTP)-Exchange Factor (GEF) that is crucial for ROP protein maturation and processing, and its loss leads to a reduced number of rhoptries
Vps[9] domain-containing proteins are known as guanine nucleotide exchange factors (GEF) that stimulate the release of monomeric guanosine diphosphate (GDP)-bound to Rab[5], allowing guanosine triphosphate (GTP) to bind and activate Rab[5] that, in turn, regulates endosome vesicle trafficking[16,17,18]

Summary

Introduction

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. 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. Dynamin-related protein B (DrpB) and clathrin, which reside in the post-Golgi network (TGN) and the endosomal-like compartment (ELC) contribute to the formation of transport vesicles that are essential for secretory organelle biogenesis[11,12]. Together with the rhoptry defect, absence of peripheral microneme formation and dense granule secretion severely affects parasite invasion of host cells. These observations support the notion that TgVps9-mediated loading of GTP to TgRab[5] is crucial for fine-tuning vesicle sorting to secretory organelles, the latter being essential for T. gondii host cell infection

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Results

Conclusion