title: The orphan nuclear receptor TR3/Nur77 regulates ER stress and induces apoptosis via interaction with TRAPγ.
abstract: 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.
authors: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, PR China. chenhz@xmu.edu.cn
authors: Hang-zi
authors: HZ
authors: Chen
authors: Quan
authors: Q
authors: Wen
authors: Wei-jia
authors: WJ
authors: Wang
authors: Jian-ping
authors: JP
authors: He
authors: Qiao
authors: Q
authors: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: C099555:CD 437; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; D012176:Retinoids; C066973:signal sequence receptor; D014415:Tunicamycin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium
keywords: Apoptosis; Ca(2+) depletion; ER stress; Orphan nuclear receptor TR3/Nur77; Translocon-associated protein TRAPγ