Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is critical for mediating Toll-like receptor (TLR)-interleukin 1 receptor (IL-1R) signaling and subsequent activation of NF-kappaB and AP-1, transcriptional activators of innate immunity. Here we show that beta-arrestins, a family of multifunctional proteins, directly interacted with TRAF6 after TLR-IL-1R activation. Formation of the beta-arrestin-TRAF6 complex prevented autoubiquitination of TRAF6 and activation of NF-kappaB and AP-1. Endotoxin-treated beta-arrestin 2-deficient mice had higher expression of proinflammatory cytokines and were more susceptible to endotoxic shock. Thus, beta-arrestins are essential negative regulators of innate immune activation via TLR-IL-1R signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arrestins / deficiency
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Arrestins / genetics
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Arrestins / metabolism*
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Binding Sites
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Cell Line
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Cytokines / biosynthesis
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Female
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HeLa Cells
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Humans
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Immunity, Innate
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Interleukin-1 / pharmacology
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Signal Transduction
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TNF Receptor-Associated Factor 6 / metabolism*
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Toll-Like Receptor 1 / metabolism*
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Transcription Factor AP-1 / antagonists & inhibitors
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Transcription Factor AP-1 / metabolism
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Ubiquitin / metabolism
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beta-Arrestin 2
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beta-Arrestins
Substances
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ARRB2 protein, human
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Arrb2 protein, mouse
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Arrestins
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Cytokines
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Interleukin-1
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Lipopolysaccharides
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NF-kappa B
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 1
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Transcription Factor AP-1
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Ubiquitin
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beta-Arrestin 2
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beta-Arrestins