title: Pirk is a negative regulator of the Drosophila Imd pathway.
abstract: NF-kappaB transcription factors are involved in evolutionarily conserved signaling pathways controlling multiple cellular processes including apoptosis and immune and inflammatory responses. Immune response of the fruit fly Drosophila melanogaster to Gram-negative bacteria is primarily mediated via the Imd (immune deficiency) pathway, which closely resembles the mammalian TNFR signaling pathway. Instead of cytokines, the main outcome of Imd signaling is the production of antimicrobial peptides. The pathway activity is delicately regulated. Although many of the Imd pathway components are known, the mechanisms of negative regulation are more elusive. In this study we report that a previously uncharacterized gene, pirk, is highly induced upon Gram-negative bacterial infection in Drosophila in vitro and in vivo. pirk encodes a cytoplasmic protein that coimmunoprecipitates with Imd and the cytoplasmic tail of peptidoglycan recognition protein LC (PGRP-LC). RNA interference-mediated down-regulation of Pirk caused Imd pathway hyperactivation upon infection with Gram-negative bacteria, while overexpression of pirk reduced the Imd pathway response both in vitro and in vivo. Furthermore, pirk-overexpressing flies were more susceptible to Gram-negative bacterial infection than wild-type flies. We conclude that Pirk is a negative regulator of the Imd pathway.
authors.affiliation: Institute of Medical Technology, University of Tampere, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Kleino
authors.forename: Henna
authors.initials: H
authors.lastname: Myllymäki
authors.forename: Jenni
authors.initials: J
authors.lastname: Kallio
authors.forename: Leena-Maija
authors.initials: LM
authors.lastname: Vanha-aho
authors.forename: Kaisa
authors.initials: K
authors.lastname: Oksanen
authors.forename: Johanna
authors.initials: J
authors.lastname: Ulvila
authors.forename: Dan
authors.initials: D
authors.lastname: Hultmark
authors.forename: Susanna
authors.initials: S
authors.lastname: Valanne
authors.forename: Mika
authors.initials: M
authors.lastname: Rämet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D016972:Enterobacter cloacae / Q000276:immunology* / Q000502:physiology; D017344:Genes, Insect; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D016328:NF-kappa B; C532213:Pirk protein, Drosophila; C439909:imd protein, Drosophila; C118897:peptidoglycan recognition protein