The orphan nuclear receptor TR3/Nur77 regulates ER stress and induces apoptosis via interaction with TRAPγ

Int J Biochem Cell Biol. 2013 Aug;45(8):1600-9. doi: 10.1016/j.biocel.2013.04.026. Epub 2013 May 6.


The orphan nuclear receptor TR3 (also known as Nur77) belongs to the steroid/thyroid/retinoid nuclear receptor superfamily and plays important roles in regulating cell proliferation, differentiation and apoptosis. No physiological ligand for TR3 has been found thus far; the determination of its binding partners is therefore important to clarify the biological functions of TR3. Here, we identified translocon-associated protein subunit γ (TRAPγ) as a novel TR3 binding partner using a tandem affinity purification method. This interaction between TR3 and TRAPγ was further confirmed, and the interacting regions were mapped. The ligand-binding domain of TR3 was required for TRAPγ binding, and the C terminus of TRAPγ was responsible for its interaction with TR3. When stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or CD437, this TR3-TRAPγ interaction not only induced Ca(2+) depletion in the endoplasmic reticulum (ER) but also promoted the expression of the proapoptotic transcriptional regulator CHOP. Notably, both TR3 and TRAPγ were required for ER stress-induced apoptosis in HepG2 cells. Overall, this study demonstrated a novel, TR3-initiated signaling pathway in which TR3 regulates ER stress and induces apoptosis of hepatoma cells through its interaction with TRAPγ.

Keywords: Apoptosis; Ca(2+) depletion; ER stress; Orphan nuclear receptor TR3/Nur77; Translocon-associated protein TRAPγ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism*
  • Cell Death / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress* / drug effects
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Membrane Glycoproteins / metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Protein Binding / drug effects
  • Protein Interaction Mapping
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Peptide / metabolism*
  • Retinoids / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tunicamycin / pharmacology


  • CD 437
  • Calcium-Binding Proteins
  • Membrane Glycoproteins
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Peptide
  • Retinoids
  • signal sequence receptor
  • Tunicamycin
  • Tetradecanoylphorbol Acetate
  • Calcium