Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α

Qiang Li; Netanya Y Spencer; Fredrick D Oakley; Garry R Buettner; John F Engelhardt

doi:10.1089/ars.2008.2407

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Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α

Journal article

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Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α

Qiang Li, Netanya Y Spencer, Fredrick D Oakley, Garry R Buettner and John F Engelhardt

Antioxidants & redox signaling, Vol.11(6), pp.1249-1263

06/2009

DOI: 10.1089/ars.2008.2407

PMCID: PMC2842115

PMID: 19113817

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Abstract

Growing evidence suggests that NADPH oxidase (Nox)-derived reactive oxygen species (ROS) play important roles in regulating cytokine signaling. We have explored how TNF-α induction of Nox-dependent ROS influences NF-κB activation. Cellular stimulation by TNF-α induced NADPH-dependent superoxide production in the endosomal compartment, and this ROS was required for IKK-mediated activation of NF-κB. Inhibiting endocytosis reduced the ability of TNF-α to induce both NADPH-dependent endosomal superoxide and NF-κB, supporting the notion that redox-dependent signaling of the receptor occurs in the endosome. Molecular analyses demonstrated that endosomal H 2 O 2 was critical for the recruitment of TRAF2 to the TNFR1/TRADD complex after endocytosis. Studies using both Nox2 siRNA and Nox2-knockout primary fibroblasts indicated that Nox2 was critical for TNF-α–mediated induction of endosomal superoxide. Redox-active endosomes that form after TNF-α or IL-1β induction recruit several common proteins (Rac1, Nox2, p67 phox , SOD1), while also retaining specificity for ligand-activated receptor effectors. Our studies suggest that TNF-α and IL-1β signaling pathways both can use Nox2 to facilitate redox activation of their respective receptors at the endosomal level by promoting the redox-dependent recruitment of TRAFs. These studies help to explain how cellular compartmentalization of redox signals can be used to direct receptor activation from the plasma membrane. Antioxid. Redox Signal. 11, 1249–1263.

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Details

Title: Subtitle: Endosomal Nox2 Facilitates Redox-Dependent Induction of NF-κB by TNF-α
Creators: Qiang Li - Department of Anatomy and Cell Biology, Carver College of Medicine
Netanya Y Spencer - Department of Anatomy and Cell Biology, Carver College of Medicine
Fredrick D Oakley - Department of Anatomy and Cell Biology, Carver College of Medicine
Garry R Buettner - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine
John F Engelhardt - Department of Anatomy and Cell Biology, Carver College of Medicine
Resource Type: Journal article
Publication Details: Antioxidants & redox signaling, Vol.11(6), pp.1249-1263
DOI: 10.1089/ars.2008.2407
PMID: 19113817
PMCID: PMC2842115
NLM abbreviation: Antioxid Redox Signal
ISSN: 1523-0864
eISSN: 1557-7716
Publisher: Mary Ann Liebert, Inc
Language: English
Date published: 06/2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025351402771

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