Control of Hepatic Nuclear Superoxide Production by Glucose 6-Phosphate Dehydrogenase and NADPH Oxidase-4

Netanya Y Spencer; Ziying Yan; Ryan L Boudreau; Yulong Zhang; Meihui Luo; Qiang Li; Xin Tian; Ajay M Shah; Robin L Davisson; Beverly Davidson; Botond Banfi; John F Engelhardt

doi:10.1074/jbc.M110.193821

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Control of Hepatic Nuclear Superoxide Production by Glucose 6-Phosphate Dehydrogenase and NADPH Oxidase-4

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Control of Hepatic Nuclear Superoxide Production by Glucose 6-Phosphate Dehydrogenase and NADPH Oxidase-4

Netanya Y Spencer, Ziying Yan, Ryan L Boudreau, Yulong Zhang, Meihui Luo, Qiang Li, Xin Tian, Ajay M Shah, Robin L Davisson, Beverly Davidson, …

The Journal of biological chemistry, Vol.286(11), pp.8977-8987

03/18/2011

DOI: 10.1074/jbc.M110.193821

PMCID: PMC3059029

PMID: 21212270

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Abstract

Redox-regulated signal transduction is coordinated by spatially controlled production of reactive oxygen species within subcellular compartments. The nucleus has long been known to produce superoxide (O 2 ⨪ ); however, the mechanisms that control this function remain largely unknown. We have characterized molecular features of a nuclear superoxide-producing system in the mouse liver. Using electron paramagnetic resonance, we investigated whether several NADPH oxidases (NOX1, 2, and 4) and known activators of NOX (Rac1, Rac2, p22 phox , and p47 phox ) contribute to nuclear O 2 ⨪ production in isolated hepatic nuclei. Our findings demonstrate that NOX4 most significantly contributes to hepatic nuclear O 2 ⨪ production that utilizes NADPH as an electron donor. Although NOX4 protein immunolocalized to both nuclear membranes and intranuclear inclusions, fluorescent detection of NADPH-dependent nuclear O 2 ⨪ predominantly localized to the perinuclear space. Interestingly, NADP + and G6P also induced nuclear O 2 ⨪ production, suggesting that intranuclear glucose-6-phosphate dehydrogenase (G6PD) can control NOX4 activity through nuclear NADPH production. Using G6PD mutant mice and G6PD shRNA, we confirmed that reductions in nuclear G6PD enzyme decrease the ability of hepatic nuclei to generate O 2 ⨪ in response to NADP + and G6P. NOX4 and G6PD protein were also observed in overlapping microdomains within the nucleus. These findings provide new insights on the metabolic pathways for substrate regulation of nuclear O 2 ⨪ production by NOX4.

Nucleus

Nuclear Membrane

Superoxide Ion

Signal Transduction

Hepatocyte

Liver

Details

Title: Subtitle: Control of Hepatic Nuclear Superoxide Production by Glucose 6-Phosphate Dehydrogenase and NADPH Oxidase-4
Creators: Netanya Y Spencer - From the Departments of
Ziying Yan - From the Departments of
Ryan L Boudreau - Internal Medicine and
Yulong Zhang - From the Departments of
Meihui Luo - From the Departments of
Qiang Li - From the Departments of
Xin Tian - From the Departments of
Ajay M Shah - King's College London British Heart Foundation Centre, London SE5 9NU, United Kingdom, and
Robin L Davisson - the
Beverly Davidson - Internal Medicine and
Botond Banfi - From the Departments of
John F Engelhardt - From the Departments of
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(11), pp.8977-8987
DOI: 10.1074/jbc.M110.193821
PMID: 21212270
PMCID: PMC3059029
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: R01 DK051315; K01 DK083429 / National Institutes of Health
Alternative title: Regulation of Nuclear Superoxide Production in Mouse Liver
Language: English
Date published: 03/18/2011
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Otolaryngology; Internal Medicine
Record Identifier: 9984025373502771

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