Tumor Necrosis Factor Receptor-1 Can Function through a Gαq/11-β-Arrestin-1 Signaling Complex

Yuji Kawamata,Takeshi Imamura,Jennie L Babendure,Juu-Chin Lu,Takeshi Yoshizaki,Jerrold M Olefsky

doi:10.1074/jbc.m705869200

Yuji Kawamata, Takeshi Imamura + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m705869200

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Abstract

Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine secreted from macrophages and adipocytes. It is well known that chronic TNFalpha exposure can lead to insulin resistance both in vitro and in vivo and that elevated blood levels of TNFalpha are observed in obese and/or diabetic individuals. TNFalpha has many acute biologic effects, mediated by a complex intracellular signaling pathway. In these studies we have identified new G-protein signaling components to this pathway in 3T3-L1 adipocytes. We found that beta-arrestin-1 is associated with TRAF2 (TNF receptor-associated factor 2), an adaptor protein of TNF receptors, and that TNFalpha acutely stimulates tyrosine phosphorylation of G alpha(q/11) with an increase in G alpha(q/11) activity. Small interfering RNA-mediated knockdown of beta-arrestin-1 inhibits TNFalpha-induced tyrosine phosphorylation of G alpha(q/11) by interruption of Src kinase activation. TNFalpha stimulates lipolysis in 3T3-L1 adipocytes, and beta-arrestin-1 knockdown blocks the effects of TNFalpha to stimulate ERK activation and glycerol release. TNFalpha also led to activation of JNK with increased expression of the proinflammatory gene, monocyte chemoattractant protein-1 and matrix metalloproteinase 3, and beta-arrestin-1 knockdown inhibited both of these effects. Taken together these results reveal novel elements of TNFalpha action; 1) the trimeric G-protein component G alpha(q/11) and the adapter protein beta-arrestin-1 can function as signaling molecules in the TNFalpha action cascade; 2) beta-arrestin-1 can couple TNFalpha stimulation to ERK activation and lipolysis; 3) beta-arrestin-1 and G alpha(q/11) can mediate TNFalpha-induced phosphatidylinositol 3-kinase activation and inflammatory gene expression.

Highlights

Based on these facts, we sought to determine whether TNF␣ signaling could couple with G-protein components to mediate biologic effects
In this report we show that in 3T3-L1 adipocytes, TNF␣ signals through the TNF-R11⁄7TRAF2 receptor complex and that this can couple into a trimeric G-protein G␣q/11 and an adaptor protein ␤-arrestin-1 to mediate TNF␣ activation of ERK, lipolysis, and stimulation of the proinflammatory pathway
The G-protein Signaling Component, ␤-Arrestin-1, Couples with the TNF Receptor Complex—␤-Arrestin-1 is a scaffold protein that functions in a number of 7-transmembrane (TM) receptors (7-TMRs) signaling pathways, and TRAF2 serves as an adaptor protein for TNF␣ signaling

Summary

Introduction

We sought to determine whether TNF␣ signaling could couple with G-protein components to mediate biologic effects. In this report we show that in 3T3-L1 adipocytes, TNF␣ signals through the TNF-R11⁄7TRAF2 receptor complex and that this can couple into a trimeric G-protein G␣q/11 and an adaptor protein ␤-arrestin-1 to mediate TNF␣ activation of ERK, lipolysis, and stimulation of the proinflammatory pathway.

Results

Conclusion