Lipid Rafts and Caveolin-1 Coordinate Interleukin-1β (IL-1β)-dependent Activation of NFκB by Controlling Endocytosis of Nox2 and IL-1β Receptor 1 from the Plasma Membrane

Fredrick D Oakley; Rachel L Smith; John F Engelhardt

doi:10.1074/jbc.M109.042127

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Lipid Rafts and Caveolin-1 Coordinate Interleukin-1β (IL-1β)-dependent Activation of NFκB by Controlling Endocytosis of Nox2 and IL-1β Receptor 1 from the Plasma Membrane

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Lipid Rafts and Caveolin-1 Coordinate Interleukin-1β (IL-1β)-dependent Activation of NFκB by Controlling Endocytosis of Nox2 and IL-1β Receptor 1 from the Plasma Membrane

Fredrick D Oakley, Rachel L Smith and John F Engelhardt

The Journal of biological chemistry, Vol.284(48), pp.33255-33264

11/27/2009

DOI: 10.1074/jbc.M109.042127

PMCID: PMC2785168

PMID: 19801678

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Abstract

Recent evidence suggests that signaling by the proinflammatory cytokine interleukin-1β (IL-1β) is dependent on reactive oxygen species derived from NADPH oxidase. Redox signaling in response to IL-1β is known to require endocytosis of its cognate receptor (IL-1R1) following ligand binding and the formation of redox-active signaling endosomes that contain Nox2 (also called redoxosomes). The consequent generation of reactive oxygen species by redoxosomes is responsible for the downstream recruitment of IL-1R1 effectors (IRAK, TRAF6, and IκB kinase kinases) and ultimately for activation of the transcription factor NFκB. Despite this knowledge of the signaling events that occur downstream of redoxosome formation, an understanding of the mechanisms that coordinate the genesis of redoxosomes following IL-1β stimulation has been lacking. Here, we demonstrate that lipid rafts play an important role in this process. We show that Nox2 and IL-1R1 localize to plasma membrane lipid rafts in the unstimulated state and that IL-1β signals caveolin-1-dependent endocytosis of both proteins into the redoxosome. We also show that inhibiting lipid raft-mediated endocytosis prevents NFκB activation. Finally, we demonstrate that Vav1, a Rac1 guanine exchange factor and activator of Nox2, is recruited to lipid rafts following IL-1β stimulation and that it is required for NFκB activation. Our results fill in an important mechanistic gap in the understanding of early IL-1R1 and Nox2 signaling events that control NFκB activation, a redox-dependent process important in inflammation.

Mechanisms of Signal Transduction

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Title: Subtitle: Lipid Rafts and Caveolin-1 Coordinate Interleukin-1β (IL-1β)-dependent Activation of NFκB by Controlling Endocytosis of Nox2 and IL-1β Receptor 1 from the Plasma Membrane
Creators: Fredrick D Oakley - From the Departments of
Rachel L Smith - From the Departments of
John F Engelhardt - From the Departments of
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.284(48), pp.33255-33264
DOI: 10.1074/jbc.M109.042127
PMID: 19801678
PMCID: PMC2785168
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 DK067928; R01 DK051315; P30 DK54759 / National Institutes of Health
Language: English
Date published: 11/27/2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025303102771

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