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NF‐κB directly regulates β‐arrestin‐1 expression and forms a negative feedback circuit in TNF‐α‐induced cell death
Author(s) -
Li Juan,
Guo Ao,
Wang Qinying,
Li Yuanyuan,
Zhao Jian,
Lu Jing,
Pei Gang
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700642rrr
Subject(s) - arrestin , microbiology and biotechnology , programmed cell death , nf κb , biology , embryonic stem cell , p50 , tumor necrosis factor alpha , chemistry , signal transduction , transcription factor , gene , apoptosis , endocrinology , genetics , g protein coupled receptor
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‐κBand 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. FASEB J . 32, 4096–4106 (2018). www.fasebj.org