Abstract
Shigella flexneri invades host cells by entering within a bacteria-containing vacuole (BCV). In order to establish its niche in the host cytosol, the bacterium ruptures its BCV. Contacts between S. flexneri BCV and infection-associated macropinosomes (IAMs) formed in situ have been reported to enhance BCV disintegration. The mechanism underlying S. flexneri vacuolar escape remains however obscure. To decipher the molecular mechanism priming the communication between the IAMs and S. flexneri BCV, we performed mass spectrometry-based analysis of the magnetically purified IAMs from S. flexneri-infected cells. While proteins involved in host recycling and exocytic pathways were significantly enriched at the IAMs, we demonstrate more precisely that the S. flexneri type III effector protein IpgD mediates the recruitment of the exocyst to the IAMs through the Rab8/Rab11 pathway. This recruitment results in IAM clustering around S. flexneri BCV. More importantly, we reveal that IAM clustering subsequently facilitates an IAM-mediated unwrapping of the ruptured vacuole membranes from S. flexneri, enabling the naked bacterium to be ready for intercellular spread via actin-based motility. Taken together, our work untangles the molecular cascade of S. flexneri-driven host trafficking subversion at IAMs to develop its cytosolic lifestyle, a crucial step en route for infection progression at cellular and tissue level.
Highlights
During bacterial invasion of eukaryotic cells, bacteria were internalized inside a bacteria-containing vacuole (BCV), which is manipulated to establish the intracellular replicative niche of the pathogens
Upon its entry into host cell, S. flexneri resides shortly in a bacteria-containing vacuole (BCV), which is rapidly ruptured for the cytosolic propagation and infection progression of the pathogen
We have previously demonstrated that the communication between these two compartments leads to the destabilization of S. flexneri BCV
Summary
During bacterial invasion of eukaryotic cells, bacteria were internalized inside a bacteria-containing vacuole (BCV), which is manipulated to establish the intracellular replicative niche of the pathogens. Versatile strategies are deployed by bacterial pathogens to modulate the BCV stability in order to evade the host immune response and adapt to the hostile environment of the infected host [3,4,5,6]. One such strategy is to hijack host membrane trafficking pathways. These pathways are tightly regulated by the small GTPases of the Rab family to allow the recycling of endocytosed proteins and lipids back to the plasma membrane [7]. Recycling vesicles are tethered to the plasma membrane by tethering factors, which enhances the subsequent membrane fusions mediated by soluble N-ethylmaleimidesensitive factor attachment protein receptors (SNAREs) [7, 10]
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