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Venugopal, Kannan, Chehade, Sylia, Werkmeister, Elisabeth, Barois, Nicolas, Periz, Javier, Lafont, Frank, Tardieux, Isabelle, Khalife, Jamal, Langsley, Gordon, Meissner, Markus and Marion, Sabrina (2020): Rab11A regulates dense granule transport and secretion during Toxoplasma gondii invasion of host cells and parasite replication.
In: PLOS Pathogens 16(5), e1008106 [PDF, 4MB]


Toxoplasma gondii possesses an armada of secreted virulent factors that enable parasite invasion and survival into host cells. These factors are contained in specific secretory organelles, the rhoptries, micronemes and dense granules that release their content upon host cell recognition. Dense granules are secreted in a constitutive manner during parasite replication and play a crucial role in modulating host metabolic and immune responses. While the molecular mechanisms triggering rhoptry and microneme release upon host cell adhesion have been well studied, constitutive secretion remains a poorly explored aspect of T. gondii vesicular trafficking. Here, we investigated the role of the small GTPase Rab11A, a known regulator of exocytosis in eukaryotic cells. Our data revealed an essential role of Rab11A in promoting the cytoskeleton driven transport of dense granules and the release of their content into the vacuolar space. Rab11A also regulates transmembrane protein trafficking and localization during parasite replication, indicating a broader role of Rab11A in cargo exocytosis at the plasma membrane. Moreover, we found that Rab11A also regulates extracellular parasite motility and adhesion to host cells. In line with these findings, MIC2 secretion was altered in Rab11A-defective parasites, which also exhibited severe morphological defects. Strikingly, by live imaging we observed a polarized accumulation of Rab11A-positive vesicles and dense granules at the apical pole of extracellular motile and invading parasites suggesting that apically polarized Rab11A-dependent delivery of cargo regulates early secretory events during parasite entry into host cells. Author summary Toxoplasma gondii (T. gondii) is a highly prevalent parasite infecting a wide range of animals as well as humans. T. gondii secretes numerous virulent factors contained in specific organelles, termed the rhoptries, micronemes and dense granules. These factors are released upon host cell recognition and enable parasite invasion and subsequent development into an intracellular vacuole. In particular, dense granules contain critical effectors that modulate intrinsic defenses of infected host cells ensuring parasite survival and dissemination. The mechanisms regulating dense granule secretion have not been elucidated. In this study, we unraveled a novel role for the T. gondii GTPase Rab11A in promoting dense granule transport along the parasite cytoskeleton and their content release into the vacuolar space during parasite replication. We also found that T. gondii Rab11A regulates extracellular parasite motility and adhesion to host cells suggesting a broader role in distinct secretory pathways essential for parasite virulence.

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