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

dc.contributor.author

Suliman, Hagir B

dc.contributor.author

Sweeney, Timothy E

dc.contributor.author

Withers, Crystal M

dc.contributor.author

Piantadosi, Claude A

dc.coverage.spatial

England

dc.date.accessioned

2011-06-21T17:27:35Z

dc.date.issued

2010-08-01

dc.description.abstract

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.

dc.description.version

Version of Record

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/20587593

dc.identifier

jcs.064089

dc.identifier.eissn

1477-9137

dc.identifier.uri

https://hdl.handle.net/10161/4185

dc.language

eng

dc.language.iso

en_US

dc.publisher

The Company of Biologists

dc.relation.ispartof

J Cell Sci

dc.relation.isversionof

10.1242/jcs.064089

dc.relation.journal

Journal of cell science

dc.subject

Animals

dc.subject

Chromatin Immunoprecipitation

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Computational Biology

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Cyclic AMP Response Element-Binding Protein

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DNA, Mitochondrial

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Electrophoretic Mobility Shift Assay

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Hep G2 Cells

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Humans

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Immunoblotting

dc.subject

Inflammation

dc.subject

Introns

dc.subject

Lipopolysaccharides

dc.subject

Male

dc.subject

Mice

dc.subject

Mice, Inbred C57BL

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Mitochondria

dc.subject

NF-kappa B

dc.subject

Nitriles

dc.subject

Nuclear Respiratory Factor 1

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Promoter Regions, Genetic

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Protein Binding

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Sulfones

dc.title

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

dc.title.alternative
dc.type

Journal article

duke.date.pubdate

2010-8-1

duke.description.issue

15

duke.description.volume

123

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/20587593

pubs.begin-page

2565

pubs.end-page

2575

pubs.issue

Pt 15

pubs.organisational-group

Anesthesiology

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Medicine

pubs.organisational-group

Medicine, Pulmonary, Allergy, and Critical Care Medicine

pubs.organisational-group

Pathology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

123

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