Vibrio Effector Protein, VopQ Targets the Host Lysosome to Manipulate Autophagy




Sreelatha, Anju

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Vibrio parahaemolyticus is a gram-negative marine bacterium that is the major cause of gastroenteritis due to the consumption of contaminated raw or undercooked seafood. Vibrio parahaemolyticus harbors two Type III secretion systems. The first, T3SS1, orchestrates a temporally regulated cell death mediated by autophagy, membrane blebbing, followed by cell rounding and eventual lysis of the host cell. One T3SS1 effector protein, VopQ is both necessary and sufficient to induce rapid autophagy during the first hour of infection. Herein, I characterize the biochemical activity of the virulence factor VopQ, a novel Vibrio parahaemolyticus protein with no homology to any proteins outside of the Vibrio species. VopQ binds to the conserved Vo domain of the V-ATPase that is enriched on the lysosomal membrane and causes deacidification of the lysosomes within minutes of entry into the host cell. VopQ forms an ~18 angstrom gated channel that facilitates outward-rectified flux of ions across lipid bilayers. These studies show how a bacterial pathogen uses a novel, targeted pore forming effector to alter autophagic flux by manipulating the partitioning of small molecules and ions. Additionally, we demonstrate that VopQ is also a potent inhibitor of vesicular membrane fusion using in vitro membrane fusion. The inhibition of membrane fusion appears to be independent of VopQ’s pore-forming activity. VopQ inhibits the final step of membrane fusion by inhibiting trans-SNARE complex formation. In order to delineate the two inhibitory functions of VopQ, deacidification and membrane fusion, I use mutational, biochemical and crystallographic studies. Elucidating the molecular mechanism of VopQ not only provides a better understanding of Vibrio parahaemolyticus pathology but also offers new insight into the host cell mechanisms of autophagy and vesicle fusion.

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