BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of endoplasmic reticulum stress transducer
BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of endoplasmic reticulum stress transducer
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DOI：
10.1128/mcb.01552-06
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发表时间：
2007-03-01
影响因子：
5.3
通讯作者：
Imaizumi, Kazunori
中科院分区：
文献类型：
--
作者：
Kondo, Shinichi;Saito, Atsushi;Imaizumi, Kazunori
内质网（ER）应激转导子IRE 1（肌醇需要1）、PERK（PKR样内质网激酶）和ATF 6（激活转录因子6）是众所周知的，当未折叠的蛋白质在ER中积累时，它们将信号从ER传递到细胞质和细胞核。最近，我们确定OASIS（旧星形胶质细胞特异性诱导物质）作为一种新的ER应激传感器在星形胶质细胞中表达。我们在这里报告，BBF 2 H7（BBF 2人类同源染色体7），ER-居民的跨膜蛋白与bZIP结构域的细胞质部分和结构同源的OASIS，被切割在膜响应ER应力。BBF 2 H7的切割片段易位到细胞核中，并可直接结合到环状AMP反应元件位点以激活靶基因的转录。有趣的是，虽然BBF 2 H7蛋白在正常条件下不表达，但在ER应激期间，它在翻译水平上被显著诱导，这表明BBF 2 H7可能仅对未折叠蛋白应答信号传导的晚期有贡献。在局灶性脑缺血的小鼠模型中，在梗塞周围区域的神经元中显著诱导BBF 2 H7蛋白。此外，在神经母细胞瘤细胞系中，BBF 2 H7过表达抑制ER应激诱导的细胞死亡，而BBF 2 H7的小干扰RNA敲低促进ER应激诱导的细胞死亡。总而言之，我们的研究结果表明BBF 2 H7是一种新型的ER应激转换器，并且在防止受损神经元中未折叠蛋白的积累方面发挥重要作用。
Endoplasmic reticulum (ER) stress transducers IRE1 (inositol requiring 1), PERK (PKR-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6) are well known to transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. Recently, we identified OASIS (old astrocyte specifically induced substance) as a novel ER stress transducer expressed in astrocytes. We report here that BBF2H7 (BBF2 human homolog on chromosome 7), an ER-resident transmembrane protein with the bZIP domain in the cytoplasmic portion and structurally homologous to OASIS, is cleaved at the membrane in response to ER stress. The cleaved fragments of BBF2H7 translocate into the nucleus and can bind directly to cyclic AMP-responsive element sites to activate transcription of target genes. Interestingly, although BBF2H7 protein is not expressed under normal conditions, it is markedly induced at the translational level during ER stress, suggesting that BBF2H7 might contribute to only the late phase of unfolded protein response signaling. In a mouse model of focal brain ischemia, BBF2H7 protein is prominently induced in neurons in the peri-infarction region. Furthermore, in a neuroblastoma cell line, BBF2H7 overexpression suppresses ER stress-induced cell death, while small interfering RNA knockdown of BBF2H7 promotes ER stress-induced cell death. Taken together, our results suggest that BBF2H7 is a novel ER stress transducer and could play important roles in preventing accumulation of unfolded proteins in damaged neurons.