title: VP1686, a Vibrio type III secretion protein, induces toll-like receptor-independent apoptosis in macrophage through NF-kappaB inhibition.
abstract: Vibrio parahaemolyticus, causative agent of human gastrointestinal diseases, possesses several virulent machineries including thermostable direct hemolysin and type III secretion systems (TTSS1 and -2). In this report, we establish that TTSS1-dependent secretion and translocation of a V. parahaemolyticus effector protein VP1686 into the cytosol induces DNA fragmentation in macrophages. We performed yeast two-hybrid screening to identify the molecules involved in VP1686-mediated cell death pathways and showed that nuclear factor RelA p65/NF-kappaB physically interacts with VP1686. To understand the impact of this interaction on the NF-kappaB DNA binding activities in infected macrophages, we analyzed a series of deletion mutants for the TTSS and its secreted proteins. Induction of DNA binding activity of NF-kappaB was significantly suppressed, and increased macrophage apoptosis has been associated with V. parahaemolyticus strain, which contains both VP1686 and TTSS1. Macrophages lacking Toll-like receptor adaptor molecules MyD88 (myeloid differentiation primary response protein 88) or TRIF (TIR domain-containing adapter-inducing interferon beta) showed similar sensitivity to VP1686. As a consequence of NF-kappaB suppression, microarray analysis has revealed that VP1686 translocation alerted the expression of many genes that have known functions in cellular responses to apoptosis, cell growth, and transcriptional regulation. Our results suggest an important role for Vibrio effector protein VP1686 that activate a conserved apoptotic pathway in macrophages through suppression of NF-kappaB activation independent of Toll-like receptor signaling.
authors.affiliation: Akira Innate Immunity Project, Exploratory Research for Advance Technology, Japan Science and Technology Agency, Osaka 565-0871, Japan.
authors.forename: Rabindra N
authors.initials: RN
authors.lastname: Bhattacharjee
authors.forename: Kwon-Sam
authors.initials: KS
authors.lastname: Park
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Okada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsui
authors.forename: Himanshu
authors.initials: H
authors.lastname: Kumar
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Iida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Honda
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D017353:Gene Deletion; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D014733:Vibrio / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D016328:NF-kappa B; D051193:Toll-Like Receptors