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A Novel Interaction between β‐arrestins and Nuclear Steroid Receptors
Author(s) -
Petrillo Maria Grazia,
Cidlowski John A
Publication year - 2017
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/fasebj.31.1_supplement.616.1
Subject(s) - arrestin , g protein coupled receptor , microbiology and biotechnology , glucocorticoid receptor , biology , transcription factor , signal transduction , pelp 1 , nuclear receptor , nuclear receptor coactivator 2 , ubiquitin , proteasome , receptor , gene , genetics
The β‐arrestin proteins play a well established role in the dampening of G‐protein coupled receptor (GPCR) signaling. In addition to being negative regulators of GPCRs, β‐arrestins are being increasingly appreciated as scaffold proteins, thus conferring novel signaling properties independent from GPCRs activity. By acting as scaffolds, the β‐arrestins interface with several proteins, thus generating a new wave of signaling pathways, including interfering with the ubiquitin‐proteasome machinery, and altering gene transcription. Recent studies have demonstrated that glucocorticoids (GCs) can regulate the transcription of β‐arrestin proteins, thereby contributing in redirecting the GPCR signaling profile. Glucocorticoid responses are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor family. By binding specific DNA responsive elements, the glucocorticoid receptor activates or represses the transcription of target genes, thus regulating numerous physiological processes, including development, metabolism, and immune response. We have recently discovered that β‐arrestin‐1 can interact with the glucocorticoid receptor. This finding led us to investigate the possibility that β‐arrestin‐1 may alter the activity of the glucocorticoid receptor. Whole transcriptome sequencing revealed that β‐arrestin‐1 has a wide impact on the glucocorticoid receptor signaling. The transcriptome analysis identified post‐translational modification as one of the top‐ranked cellular functions significantly altered by the lack of β‐arrestin‐1. Moreover, within the subset of genes enriched for post‐translational modification, lack of β‐arrestin‐1 reshaped the GR gene signature, regulating genes responsible for the activation of the ubiquitin‐proteasome machinery. In vitro data revealed that β‐arrestin‐1 affects glucocorticoid‐induced GR downregulation by altering its expression and controlling its proteasome‐mediated degradation. These results indicate a novel protein partnership between glucocorticoid receptor and β‐arrestin‐1. Support or Funding Information National Institute of Health (NIH)