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Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.

Publication ,  Journal Article
Suliman, HB; Sweeney, TE; Withers, CM; Piantadosi, CA
Published in: J Cell Sci
August 1, 2010

The nuclear respiratory factor-1 (NRF1) gene is activated by lipopolysaccharide (LPS), which might reflect TLR4-mediated mitigation of cellular inflammatory damage via initiation of mitochondrial biogenesis. To test this hypothesis, we examined NRF1 promoter regulation by NFκB, and identified interspecies-conserved κB-responsive promoter and intronic elements in the NRF1 locus. In mice, activation of Nrf1 and its downstream target, Tfam, by Escherichia coli was contingent on NFκB, and in LPS-treated hepatocytes, NFκB served as an NRF1 enhancer element in conjunction with NFκB promoter binding. Unexpectedly, optimal NRF1 promoter activity after LPS also required binding by the energy-state-dependent transcription factor CREB. EMSA and ChIP assays confirmed p65 and CREB binding to the NRF1 promoter and p65 binding to intron 1. Functionality for both transcription factors was validated by gene-knockdown studies. LPS regulation of NRF1 led to mtDNA-encoded gene expression and expansion of mtDNA copy number. In cells expressing plasmid constructs containing the NRF-1 promoter and GFP, LPS-dependent reporter activity was abolished by cis-acting κB-element mutations, and nuclear accumulation of NFκB and CREB demonstrated dependence on mitochondrial H(2)O(2). These findings indicate that TLR4-dependent NFκB and CREB activation co-regulate the NRF1 promoter with NFκB intronic enhancement and redox-regulated nuclear translocation, leading to downstream target-gene expression, and identify NRF-1 as an early-phase component of the host antibacterial defenses.

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Published In

J Cell Sci

DOI

EISSN

1477-9137

Publication Date

August 1, 2010

Volume

123

Issue

Pt 15

Start / End Page

2565 / 2575

Location

England

Related Subject Headings

  • Sulfones
  • Protein Binding
  • Promoter Regions, Genetic
  • Nuclear Respiratory Factor 1
  • Nitriles
  • NF-kappa B
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Suliman, H. B., Sweeney, T. E., Withers, C. M., & Piantadosi, C. A. (2010). Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis. J Cell Sci, 123(Pt 15), 2565–2575. https://doi.org/10.1242/jcs.064089
Suliman, Hagir B., Timothy E. Sweeney, Crystal M. Withers, and Claude A. Piantadosi. “Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.J Cell Sci 123, no. Pt 15 (August 1, 2010): 2565–75. https://doi.org/10.1242/jcs.064089.
Suliman HB, Sweeney TE, Withers CM, Piantadosi CA. Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis. J Cell Sci. 2010 Aug 1;123(Pt 15):2565–75.
Suliman, Hagir B., et al. “Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis.J Cell Sci, vol. 123, no. Pt 15, Aug. 2010, pp. 2565–75. Pubmed, doi:10.1242/jcs.064089.
Suliman HB, Sweeney TE, Withers CM, Piantadosi CA. Co-regulation of nuclear respiratory factor-1 by NFkappaB and CREB links LPS-induced inflammation to mitochondrial biogenesis. J Cell Sci. 2010 Aug 1;123(Pt 15):2565–2575.
Journal cover image

Published In

J Cell Sci

DOI

EISSN

1477-9137

Publication Date

August 1, 2010

Volume

123

Issue

Pt 15

Start / End Page

2565 / 2575

Location

England

Related Subject Headings

  • Sulfones
  • Protein Binding
  • Promoter Regions, Genetic
  • Nuclear Respiratory Factor 1
  • Nitriles
  • NF-kappa B
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male