한빛사 논문
Abstract
Lark Kyun Kim1, Un Yung Choi1, Hwan Sung Cho1, Jung Seon Lee1, Wook-bin Lee1, Jihyun Kim2, Kyoungsuk Jeong2, Jaewon Shim1, Jeongsil Kim-Ha2, Young-Joon Kim1*
1 Department of Biochemistry, National Creative Research Initiative Center for Genome Regulation, Yonsei University, Seoul, Korea, 2 Department of Molecular Biology, Sejong University, Seoul, Korea
The activation of several transcription factors is required for the elimination of infectious pathogens via the innate immune response. The transcription factors NF-κB, AP-1, and STAT play major roles in the synthesis of immune effector molecules during innate immune responses. However, the fact that these immune responses can have cytotoxic effects requires their tight regulation to achieve restricted and transient activation, and mis-regulation of the damping process has pathological consequences. Here we show that AP-1 and STAT are themselves the major inhibitors responsible for damping NF-κB-mediated transcriptional activation during the innate immune response in Drosophila. As the levels of dAP-1 and Stat92E increase due to continuous immune signaling, they play a repressive role by forming a repressosome complex with the Drosophila HMG protein, Dsp1. The dAP-1-, Stat92E-, and Dsp1-containing complexes replace Relish at the promoters of diverse immune effector genes by binding to evolutionarily conserved cis-elements, and they recruit histone deacetylase to inhibit transcription. Reduction by mutation of dAP-1, Stat92E, or Dsp1 results in hyperactivation of Relish target genes and reduces the viability of bacterially infected flies despite more efficient pathogen clearance. These defects are rescued by reducing the Relish copy number, thus confirming that mis-regulation of Relish, not inadequate activation of dAP-1, Stat92E, or Dsp1 target genes, is responsible for the reduced survival of the mutants. We conclude that an inhibitory effect of AP-1 and STAT on NF-κB is required for properly balanced immune responses and appears to be evolutionarily conserved.
Funding. This work was supported by a grant from the Korea Science and Engineering Foundation, Republic of Korea (F104AC010002-06A0301-00220) to JKH and from the Creative Research Initiatives Program of the Korean Ministry of Science and Technology to YJK.
Competing interests. The authors have declared that no competing interests exist.
Academic Editor: David S. Schneider, Stanford University, United States of America
Citation: Kim LK, Choi UY, Cho HS, Lee JS, Lee Wb, et al. (2007) Down-Regulation of NF- κB Target Genes by the AP-1 and STAT Complex during the Innate Immune Response in Drosophila. PLoS Biol 5(9): e238 doi:10.1371/journal.pbio.0050238
Received: August 11, 2006; Accepted: July 6, 2007; Published: September 4, 2007
Copyright: © 2007 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: AMP, antimicrobial peptide; ChIP, chromatin immunoprecipitation; Dsp, dorsal switch protein; EMSA, electrophoretic mobility shift assay; LPS/PGN, lipopolysaccharide/peptidoglycan; RNAi, RNA interference
* To whom correspondence should be addressed.
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