A potent virulence factor, cagE homologue of Actinobacillus actinomycetemcomitans, was identified via an expression cloning strategy and periodontitis-associated CD4(+)T-cells of a humanized mouse model. Through the immuno-gold labeling with transmission electron microscopy, immunofluorescent staining, in vitro co-cultures and Western blot studies, the resulting data clearly demonstrate that: (i) in CagE-homologue treated human epithelia in vitro, there are ultra-structural features of plasma membrane blebbing, sub-cellular disorganization with condensed and marginalized chromatins along the nuclear membrane, consistent with the pro-apoptotic characteristics, (ii) the disturbed membrane integrity detected above is associated with localization of the CagE proteins on target cell surface, and (iii) CagE-homologue is located in the cytoplasm of A. actinomycetemcomitans and associated with a bacterial type-IV secretion system (T4SS), suggesting that its translocation is required for secretion. Thus, CagE-homologue may be critically involved in A. actinomycetemcomitans-induced tissue destruction, inflammation and subsequent adverse immunity in periodontal pathogenesis.