Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways

Mol Cell. 2004 May 7;14(3):303-17. doi: 10.1016/s1097-2765(04)00216-3.

Abstract

Norepinephrine released by the sympathetic nerve terminals regulates the immune system primarily via its stimulation of beta(2)-adrenergic receptor (beta(2)AR), but the underlying molecular mechanisms remain to be elicited. Beta(2)AR, a well-studied G protein-coupled receptor (GPCR), is functionally regulated by beta-arrestin2, which not only causes receptor desensitization and internalization but also serves as a signaling molecule in GPCR signal transduction. Here we show that beta-arrestin2 directly interacts with IkappaBalpha (inhibitor of NF-kappaB, the key molecule in innate and adaptive immunity) and thus prevents the phosphorylation and degradation of IkappaBalpha. Consequently, beta-arrestin2 effectively modulates activation of NF-kappaB and expression of NF-kappaB target genes. Moreover, stimulation of beta(2)AR significantly enhances beta-arrestin2-IkappaBalpha interaction and greatly promotes beta-arrestin2 stabilization of IkappaBalpha, indicating that beta-arrestin2 mediates a crosstalk between beta(2)AR and NF-kappaB signaling pathways. Taken together, the current study may present a novel mechanism for regulation of the immune system by the sympathetic nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cell Line
  • Gene Expression Regulation / genetics
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism*
  • Mutation / genetics
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neuroimmunomodulation / genetics
  • Phosphorylation
  • Protein Structure, Tertiary / genetics
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / genetics
  • Sympathetic Nervous System / physiology
  • beta-Arrestins

Substances

  • Arrestins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Receptors, Adrenergic, beta-2
  • Receptors, G-Protein-Coupled
  • beta-Arrestins
  • NF-KappaB Inhibitor alpha