Abstract
Vibrio parahaemolyticus is an important pathogen that causes food-borne gastroenteritis in humans. The type III secretion system encoded on chromosome 2 (T3SS2) plays a critical role in the enterotoxic activity of V. parahaemolyticus. Previous studies have demonstrated that T3SS2 induces actin stress fibers in various epithelial cell lines during infection. This stress fiber formation is strongly related to pathogenicity, but the mechanisms that underlie T3SS2-dependent actin stress fiber formation and the main effector have not been elucidated. In this study, we identified VopO as a critical T3SS2 effector protein that activates the RhoA-ROCK pathway, which is an essential pathway for the induction of the T3SS2-dependent stress fiber formation. We also determined that GEF-H1, a RhoA guanine nucleotide exchange factor (GEF), directly binds VopO and is necessary for T3SS2-dependent stress fiber formation. The GEF-H1-binding activity of VopO via an alpha helix region correlated well with its stress fiber-inducing capacity. Furthermore, we showed that VopO is involved in the T3SS2-dependent disruption of the epithelial barrier. Thus, VopO hijacks the RhoA-ROCK pathway in a different manner compared with previously reported bacterial toxins and effectors that modulate the Rho GTPase signaling pathway.
Highlights
Vibrio parahaemolyticus is a Gram-negative halophilic bacterium that causes acute gastroenteritis in humans after the consumption of contaminated raw or undercooked seafood
Many bacterial pathogens manipulate the actin cytoskeleton of mammalian cells to establish pathogenesis via invasion, to evade killing by phagocytes, to disrupt a barrier function, and to induce inflammation caused by translocation type III secretion (T3S) effector proteins
In agreement with the results of a previous study [12], in both cell types, we observed that the formation of actin stress fibers was somewhat attenuated after infection with a vopL-deficient strain (POR-2ΔvopL) compared with the formation resulting from infection with the parent strain (POR-2)
Summary
Vibrio parahaemolyticus is a Gram-negative halophilic bacterium that causes acute gastroenteritis in humans after the consumption of contaminated raw or undercooked seafood. A T3SS is a multisubunit molecular system that delivers bacterial proteins known as effectors directly to the plasma membrane or into the cytoplasm of infected host cells. T3SS2, which is encoded on chromosome 2, is a major contributor to the enterotoxic effects observed in several animal models [4,5,6,7]. The T3SS2-related gene cluster is encoded in an 80kb pathogenicity island (Vp-PAI), which is conserved exclusively in pathogenic strains [8,9]. We demonstrated that the F-actin binding T3SS2 effector VopV is necessary for enterotoxicity [10]. During the identification of VopV, we identified several candidate effector genes that are encoded in the Vp-PAI region, but their roles in the pathogenicity of V. parahaemolyticus remain unknown. The precise pathogenic mechanisms underlying V. parahaemolyticus infections are not fully understood
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