Abstract
β-Arrestins (β-arrestin-1 and -2) are multifunctional proteins that play important roles in the regulation of inflammation and cell survival that need to be tightly controlled; however, the mechanism that underlies their gene expression is largely unclear. Here, we demonstrate that β-arrestin-1 is a transcriptional target of NF-κB. mRNA and protein levels of β-arrestin-1 were up-regulated by NF-κB inducers. Inhibition of NF-κB prevented the up-regulation of β-arrestin-1 mRNA, whereas activation of NF-κB led to increased β-arrestin-1 expression. β-Arrestin-1 promoter activity was consistently enhanced upon NF-κB activation as a result of the presence of a highly conserved κB site. β-Arrestin-1, in turn, suppressed the transcriptional activity of NF-κB by interfering with the interaction between p65 and p50. β-Arrestin-1-deficient mice displayed reduced TNF-α-induced cell death and increased expression of antiapoptotic genes. Reintroduction of β-arrestin-1, but not its mutant, which is unable to interfere with the p65-p50 interaction, into β-arrestin-deficient mouse embryonic fibroblasts partially restored sensitivity to TNF-α-induced cell death. These findings reveal NF-κB and β-arrestin-1 to be key components of a negative feedback circuit that is necessary to regulate cell death.-Li, J., Guo, A., Wang, Q., Li, Y., Zhao, J., Lu, J., Pei, G. NF-κB directly regulates β-arrestin-1 expression and forms a negative feedback circuit in TNF-α-induced cell death.