TRB3, a novel ER stress-inducible gene, is induced via ATF4–CHOP pathway and is involved in cell death

Authors

  • Nobumichi Ohoka,

    1. Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan
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  • Satoshi Yoshii,

    1. Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan
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  • Takayuki Hattori,

    1. Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan
    2. Department of Biochemistry 1, Hamamatsu University School of Medicine, Hamamatsu, Japan
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  • Kikuo Onozaki,

    1. Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan
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  • Hidetoshi Hayashi

    Corresponding author
    1. Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya, Japan
    • Corresponding author. Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuo-ku, Nagoya 467-8603, Japan. Tel./Fax: +81 52 836 3420; E-mail: hhayashi@phar.nagoya-cu.ac.jp

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Abstract

C/EBP homologous protein (CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.

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