Molecular Cell
Volume 14, Issue 3, 7 May 2004, Pages 303-317
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Article
Identification of β-Arrestin2 as a G Protein-Coupled Receptor-Stimulated Regulator of NF-κB Pathways

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Abstract

Norepinephrine released by the sympathetic nerve terminals regulates the immune system primarily via its stimulation of β2-adrenergic receptor (β2AR), but the underlying molecular mechanisms remain to be elicited. β2AR, a well-studied G protein-coupled receptor (GPCR), is functionally regulated by β-arrestin2, which not only causes receptor desensitization and internalization but also serves as a signaling molecule in GPCR signal transduction. Here we show that β-arrestin2 directly interacts with IκBα (inhibitor of NF-κB, the key molecule in innate and adaptive immunity) and thus prevents the phosphorylation and degradation of IκBα. Consequently, β-arrestin2 effectively modulates activation of NF-κB and expression of NF-κB target genes. Moreover, stimulation of β2AR significantly enhances β-arrestin2-IκBα interaction and greatly promotes β-arrestin2 stabilization of IκBα, indicating that β-arrestin2 mediates a crosstalk between β2AR and NF-κB signaling pathways. Taken together, the current study may present a novel mechanism for regulation of the immune system by the sympathetic nervous system.

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These authors contributed equally to this work.