title: Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src/NOX signaling pathway.
abstract: VvhA, a virulent factor of Vibrio (V.) vulnificus, induces acute cell death in a destructive manner. Autophagy plays an important role in cell death, but the functional role of VvhA in autophagy-related cell death has not been elucidated yet. We found that rVvhA significantly increased LC3 puncta formation and autophagic flux in promoting the cell death of human intestinal epithelial Caco-2 cells. The cell death induced by rVvhA was independent of lysosomal permeabilizaton and caspase activation. rVvhA induced rapid phosphorylation of c-Src in the membrane lipid raft, which resulted in an increased interaction between lipid raft molecule caveolin-1 and NADPH oxidase (NOX) complex Rac1 for ROS production. NOX-mediated ROS signaling induced by rVvhA increased the phosphorylation of extracellular signal-regulated kinase (ERK) and eukaryotic translation initiation factor 2α (eIF2α) which are required for mRNA expression of Atg5 and Atg16L1 involved in autophagosome formation. In an in vivo model, VvhA increased autophagy activation and paracellular permeabilization in intestinal epithelium. Collectively, the results here show that VvhA plays a pivotal role in the pathogenesis and dissemination of V. vulnificus by autophagy upregulation, through the lipid raft-mediated c-Src/NOX signaling pathway and ERK/eIF2α activation.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Song
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Hyeon Su
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Jun Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: National Research Laboratory of Molecular Microbiology and Toxicology, Department of Agricultural Biotechnology, and Center for Food Safety and Toxicology, Seoul National University, Seoul 08826, Korea.
authors.forename: Kyung Ku
authors.initials: KK
authors.lastname: Jang
authors.affiliation: National Research Laboratory of Molecular Microbiology and Toxicology, Department of Agricultural Biotechnology, and Center for Food Safety and Toxicology, Seoul National University, Seoul 08826, Korea.
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D001343:Autophagy; D001426:Bacterial Proteins / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D018938:Caco-2 Cells; D020169:Caspases / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism* / Q000382:microbiology; D008813:Mice, Inbred ICR; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014735:Vibrio Infections / Q000382:microbiology / Q000473:pathology*; D041261:Vibrio vulnificus / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D015852:Eukaryotic Initiation Factor-2; D017382:Reactive Oxygen Species; C470630:VvhA protein, Vibrio vulnificus; D019255:NADPH Oxidases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020169:Caspases