title: Bacterial uracil modulates Drosophila DUOX-dependent gut immunity via Hedgehog-induced signaling endosomes.
abstract: Genetic studies in Drosophila have demonstrated that generation of microbicidal reactive oxygen species (ROS) through the NADPH dual oxidase (DUOX) is a first line of defense in the gut epithelia. Bacterial uracil acts as DUOX-activating ligand through poorly understood mechanisms. Here, we show that the Hedgehog (Hh) signaling pathway modulates uracil-induced DUOX activation. Uracil-induced Hh signaling is required for intestinal expression of the calcium-dependent cell adhesion molecule Cadherin 99C (Cad99C) and subsequent Cad99C-dependent formation of endosomes. These endosomes play essential roles in uracil-induced ROS production by acting as signaling platforms for PLCβ/PKC/Ca2+-dependent DUOX activation. Animals with impaired Hh signaling exhibit abolished Cad99C-dependent endosome formation and reduced DUOX activity, resulting in high mortality during enteric infection. Importantly, endosome formation, DUOX activation, and normal host survival are restored by genetic reintroduction of Cad99C into enterocytes, demonstrating the important role for Hh signaling in host resistance to enteric infection.
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, South Korea.
authors: Kyung-Ah
authors: KA
authors: Lee
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea.
authors: Boram
authors: B
authors: Kim
authors: Department of Chemical Engineering, POSTECH, Pohang, Kyungbuk 790-784, South Korea.
authors: Jinhyuk
authors: J
authors: Bhin
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea.
authors: Do Hun
authors: DH
authors: Kim
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea.
authors: Hyejin
authors: H
authors: You
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, South Korea.
authors: Eun-Kyoung
authors: EK
authors: Kim
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, South Korea.
authors: Sung-Hee
authors: SH
authors: Kim
authors: Research Center for Human Natural Defense System, Yonsei University College of Medicine, Seoul 120-752, South Korea.
authors: Ji-Hwan
authors: JH
authors: Ryu
authors: Department of Chemical Engineering, POSTECH, Pohang, Kyungbuk 790-784, South Korea; Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, 711-873, South Korea.
authors: Daehee
authors: D
authors: Hwang
authors: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, South Korea. Electronic address: lwj@snu.ac.kr.
authors: Won-Jae
authors: WJ
authors: Lee
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology* / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D004330:Drosophila / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D011992:Endosomes / Q000378:metabolism*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D018928:Immunity, Mucosal; D007155:Immunologic Factors / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014498:Uracil / Q000378:metabolism*
chemical_list: C512040:Cad99c protein, Drosophila; D015820:Cadherins; D007155:Immunologic Factors; D017382:Reactive Oxygen Species; D014498:Uracil; D019255:NADPH Oxidases