title: Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation.
abstract: The innate immune system is the first line of defense encountered by invading pathogens. Delayed and/or inadequate innate immune responses can result in failure to combat pathogens, whereas excessive and/or inappropriate responses cause runaway inflammation. Therefore, immune responses are tightly regulated from initiation to resolution and are repressed during the steady state. It is well known that glycans presented on pathogens play important roles in pathogen recognition and the interactions between host molecules and microbes; however, the function of glycans of host organisms in innate immune responses is less well known. Here, we show that innate immune quiescence and strength of the immune response are controlled by host glycosylation involving a novel UDP-galactose transporter called Senju. In senju mutants, reduced expression of galactose-containing glycans resulted in hyperactivation of the Toll signaling pathway in the absence of immune challenges. Genetic epistasis and biochemical analyses revealed that Senju regulates the Toll signaling pathway at a step that converts Toll ligand Spatzle to its active form. Interestingly, Toll activation in immune-challenged wild type (WT) flies reduced the expression of galactose-containing glycans. Suppression of the degalactosylation by senju overexpression resulted in reduced induction of Toll-dependent expression of an antimicrobial peptide, Drosomycin, and increased susceptibility to infection with Gram-positive bacteria. These data suggest that Senju-mediated galactosylation suppresses undesirable Toll signaling activation during the steady state; however, Toll activation in response to infection leads to degalactosylation, which raises the immune response to an adequate level and contributes to the prompt elimination of pathogens.
authors.affiliation: Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan;
authors.forename: Miki
authors.initials: M
authors.lastname: Yamamoto-Hino
authors.affiliation: Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Muraoka
authors.affiliation: Invertebrate Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima 411-8540, Japan; and.
authors.forename: Shu
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Invertebrate Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima 411-8540, Japan; and.
authors.forename: Ryu
authors.initials: R
authors.lastname: Ueda
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan stgoto@rikkyo.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Goto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000276:immunology*; D004843:Epistasis, Genetic; D005690:Galactose / Q000737:chemistry; D006031:Glycosylation; D007107:Immune System; D007113:Immunity, Innate; D037102:Lectins / Q000737:chemistry; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D009154:Mutation; D011134:Polysaccharides / Q000737:chemistry; D011995:Recombination, Genetic; D051193:Toll-Like Receptors / Q000378:metabolism; D000099237:UDP-Galactose Translocators
chemical_list: D029721:Drosophila Proteins; D005690:Galactose; D037102:Lectins; D009004:Monosaccharide Transport Proteins; D011134:Polysaccharides; D051193:Toll-Like Receptors; D000099237:UDP-Galactose Translocators; C000600021:Senju protein, Drosophila; C068721:Tl protein, Drosophila
keywords: Toll pathway; galactose; glycosylation; innate immunity; nucleotide sugar transporter