Down-regulation of NF-κB target genes by the AP-1 and STAT complex during the innate immune response in Drosophila

Kyun Kim Lark, Yung Choi Un, Sung Cho Hwan, Seon Lee Jung, Wook Bin Lee, Jihyun Kim, Kyoungsuk Jeong, Jaewon Shim, Jeongsil Kim-Ha, Young-Joon Kim

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2064-2076
Number of pages13
JournalPLoS Biology
Volume5
Issue number9
DOIs
Publication statusPublished - 2007 Jan 1

Fingerprint

Transcription Factor AP-1
Innate Immunity
Drosophila
Down-Regulation
Genes
Chemical activation
Pathogens
Transcription Factors
transcription factors
immune response
High Mobility Group Proteins
Drosophila Proteins
histone deacetylase
Histone Deacetylases
genes
pathogens
Damping
transcriptional activation
Pathologic Processes
Diptera

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lark, Kyun Kim ; Un, Yung Choi ; Hwan, Sung Cho ; Jung, Seon Lee ; Lee, Wook Bin ; Kim, Jihyun ; Jeong, Kyoungsuk ; Shim, Jaewon ; Kim-Ha, Jeongsil ; Kim, Young-Joon. / Down-regulation of NF-κB target genes by the AP-1 and STAT complex during the innate immune response in Drosophila. In: PLoS Biology. 2007 ; Vol. 5, No. 9. pp. 2064-2076.
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Lark, KK, Un, YC, Hwan, SC, Jung, SL, Lee, WB, Kim, J, Jeong, K, Shim, J, Kim-Ha, J & Kim, Y-J 2007, 'Down-regulation of NF-κB target genes by the AP-1 and STAT complex during the innate immune response in Drosophila', PLoS Biology, vol. 5, no. 9, pp. 2064-2076. https://doi.org/10.1371/journal.pbio.0050238

Down-regulation of NF-κB target genes by the AP-1 and STAT complex during the innate immune response in Drosophila. / Lark, Kyun Kim; Un, Yung Choi; Hwan, Sung Cho; Jung, Seon Lee; Lee, Wook Bin; Kim, Jihyun; Jeong, Kyoungsuk; Shim, Jaewon; Kim-Ha, Jeongsil; Kim, Young-Joon.

In: PLoS Biology, Vol. 5, No. 9, 01.01.2007, p. 2064-2076.

Research output: Contribution to journalArticle

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AU - Lark, Kyun Kim

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AU - Hwan, Sung Cho

AU - Jung, Seon Lee

AU - Lee, Wook Bin

AU - Kim, Jihyun

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AU - Shim, Jaewon

AU - Kim-Ha, Jeongsil

AU - Kim, Young-Joon

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