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* Institute of Medical Technology, University of Tampere and
Department of Pediatrics, Tampere University Hospital, Tampere, Finland;
Department of Pediatrics, and Biocenter Oulu, University of Oulu, Oulu, Finland; and
Umeå Centre for Molecular Pathogenesis, Umeå University, Umeå, Sweden
NF-
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Academy of Finland, the Foundation for Pediatric Research, Sigrid Juselius Foundation, Emil Aaltonen Foundation, and Competitive Research Funding of the Pirkanmaa Hospital District (to M.R.), Research and Science Foundation of Farmos and Competitive Research Funding of the Pirkanmaa Hospital District (to A.K.), and the Swedish Research Council, the Swedish Foundation for Strategic Research, and the Wallenberg Consortium North (to D.H.).
2 Address correspondence and reprint requests to Dr. Mika Rämet, Institute of Medical Technology, 33014 University of Tampere, Finland. E-mail address: mika.ramet{at}uta.fi
3 Abbreviations used in this paper: PGRP, peptidoglycan recognition protein; AttB, Attacin B; CecB, Cecropin B; DptB, Diptericin B; Iap2, inhibitor of apoptosis protein 2; Imd, immune deficiency; luc, luciferase construct; Pirk, poor Imd response upon knock-in; Puc, Puckered; RNAi, RNA interference; qRT-PCR, quantitative RT-PCR; Tak1, TGF-β-activated kinase; TotM, TurandotM.
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