Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation
Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation
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DOI：
10.1038/ncb1963
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发表时间：
2009-10-01
影响因子：
21.3
通讯作者：
Imaizumi, Kazunori
中科院分区：
文献类型：
--
作者：
Murakami, Tomohiko;Saito, Atsushi;Imaizumi, Kazunori
真核细胞具有从内质网（ER）到胞质溶胶和细胞核的信号传导途径，以避免未折叠蛋白在ER中过量积累。我们先前鉴定了一种新型的ER应激转导子OASIS，它是一种bZIP（碱性亮氨酸拉链）转录因子，是CREB/ATF家族的成员，具有跨膜结构域（1-6）。OASIS通过调节膜内蛋白水解（RIP）响应ER应激进行加工，并在成骨细胞中高度表达。OASIS（-/-）小鼠表现出严重的骨量减少，包括骨基质中I型胶原减少，成骨细胞活性下降，表现为异常扩张的粗糙ER，含有大量的骨基质蛋白。在这里，我们确定了1型胶原，Col 1a 1，作为目标的OASIS的基因，并证明OASIS激活Col 1a 1的转录通过未折叠的蛋白反应元件（UPRE）样序列在成骨细胞特异性Col 1a 1启动子区。此外，OASIS在成骨细胞中的表达由BMP 2（骨形态发生蛋白2）诱导，BMP 2的信号传导是骨形成所需的。此外，OASIS的RIP被BMP 2信号传导加速，这导致轻度ER应激。我们的研究表明，OASIS通过转录Col 1a 1和分泌骨基质蛋白对骨形成至关重要，它们揭示了ER应激诱导的信号传导介导骨形成的新机制。
Eukaryotic cells have signalling pathways from the endoplasmic reticulum (ER) to cytosol and nuclei, to avoid excess accumulation of unfolded proteins in the ER. We previously identified a new type of ER stress transducer, OASIS, a bZIP (basic leucine zipper) transcription factor, which is a member of the CREB/ATF family and has a transmembrane domain(1-6). OASIS is processed by regulated intramembrane proteolysis (RIP) in response to ER stress, and is highly expressed in osteoblasts. OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type I collagen in the bone matrix and a decline in the activity of osteoblasts, which showed abnormally expanded rough ER, containing of a large amount of bone matrix proteins. Here we identify the gene for type 1 collagen, Col1a1, as a target of OASIS, and demonstrate that OASIS activates the transcription of Col1a1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter region. Moreover, expression of OASIS in osteoblasts is induced by BMP2 (bone morphogenetic protein 2), the signalling of which is required for bone formation. Additionally, RIP of OASIS is accelerated by BMP2 signalling, which causes mild ER stress. Our studies show that OASIS is critical for bone formation through the transcription of Col1a1 and the secretion of bone matrix proteins, and they reveal a new mechanism by which ER stress-induced signalling mediates bone formation.