Regulation of ER stress response by cytoplasmic mRNA splicing

通过细胞质 mRNA 剪接调节 ER 应激反应

• 批准号: 17370061
• 负责人: YOSHIDA Hiderou
• 金额: $ 9.41万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17370061/
• 关键词: stress; splicing; ER stress; cytoplasmic splicing; XBP1; IRE1; dementia; neurodegererating disease; 転写制御; ストレス応答; シャペロン; タンパク質分解; 転写因子; 蛋白質分解; フレームスイッチスプライシング

XBP1 is a key transcription factor regulating mammalian endoplasmic reticulum (ER) stress. Expression of XBP1 is mainly regulated at the level of mRNA splicing. In response to ER stress, XBP1 pre-mRNA is converted to mature mRNA, from which an active transcription factor pXBP1(S) is translated and activates ER stress response. ER stress response is involved in neurodegererating diseases including Alzheimer's disease, and clarification of the mechanism of ER stress response would be beneficial for prevention, diagnosis and treatment of such diseases.Here we revealed that splicing of XBP1 is regulated by cytoplasmic splicing instead of conventional nuclear splicing, indicating that cytoplasmic splicing is widely conserved from yeasts to mammals. We also discovered that pXBP1(U), a protein translated from unspliced XBP1 pre-mRNA, is a negative regulator of pXBP1(S). This indicates that mammalian cells rapidly switch XBP1 protein from a negative regulator to an activator in the place of translation in response to ER stress, and that this rapidity is the main reason why mammalian cells adopt cytoplasmic splicing to cope with ER stress.This study greatly contributed to the research of ER stress response. Moreover, it established a new research field of cytoplasmic splicing and evoked deep impact to the other fields such as RNA splicing. Now we plan to identify factors regulating mammalian cytoplasmic splicing to clarify the molecular mechanism.

XBP1 是调节哺乳动物内质网 (ER) 应激的关键转录因子。 XBP1的表达主要在mRNA剪接水平上受到调节。为了响应 ER 应激，XBP1 前体 mRNA 转化为成熟 mRNA，其中翻译出活性转录因子 pXBP1(S) 并激活 ER 应激反应。内质网应激反应参与包括阿尔茨海默氏病在内的神经退行性疾病，阐明内质网应激反应的机制将有益于此类疾病的预防、诊断和治疗。在此，我们发现XBP1的剪接是通过细胞质剪接而不是常规的核剪接来调节的，这表明细胞质剪接从酵母到哺乳动物都广泛保守。我们还发现 pXBP1(U) 是一种由未剪接的 XBP1 前 mRNA 翻译而来的蛋白质，是 pXBP1(S) 的负调节因子。这表明哺乳动物细胞在应对内质网应激时，在翻译处迅速将XBP1蛋白从负调节子转变为激活子，这种快速性是哺乳动物细胞采用胞质剪接来应对内质网应激的主要原因。本研究为内质网应激反应的研究做出了巨大贡献。不仅如此，它还建立了细胞质剪接的新研究领域，并对RNA剪接等其他领域产生了深远的影响。现在我们计划鉴定调节哺乳动物细胞质剪接的因素以阐明其分子机制。

项目成果

細胞質で起こるmRNAスプライシング

发生在细胞质中的 mRNA 剪接

• 发表时间: 2006
• 期刊: 蛋白質核酸酵素 51
• 作者: 神山 勉;吉村恵子;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;Hiderou Yoshida;吉田秀郎;Hiderou Yoshida;Hiderou Yoshida;Yukako Oda;Satomi Nadanaka;Satomi Nadanaka;Satomi Nadanaka;吉田秀郎
• 通讯作者: 吉田秀郎

A role of disulfide bridges formed in the lumenal domain of ATF6 in sensing endoplasmic reticulum stress.

ATF6 腔域中形成的二硫桥在感知内质网应激中的作用。

• 发表时间: 2006
• 期刊: Molecular and Cellular Biology 27
• 作者: 神山 勉;吉村恵子;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;Hiderou Yoshida;吉田秀郎;Hiderou Yoshida;Hiderou Yoshida;Yukako Oda;Satomi Nadanaka;Satomi Nadanaka;Satomi Nadanaka;吉田秀郎;吉田秀郎;Hiderou Yoshida;吉田秀郎;灘中里美
• 通讯作者: 灘中里美

細胞質スプライシング

细胞质剪接

• 发表时间: 2006
• 期刊: 生化学 78
• 作者: 神山 勉;吉村恵子;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;Hiderou Yoshida;吉田秀郎;Hiderou Yoshida;Hiderou Yoshida;Yukako Oda;Satomi Nadanaka;Satomi Nadanaka;Satomi Nadanaka;吉田秀郎;吉田秀郎
• 通讯作者: 吉田秀郎

小胞体ストレスと細胞分化の接点.

内质网应激和细胞分化之间的界面。

• 发表时间: 2005
• 期刊: 実験医学 23
• 作者: 神山 勉;吉村恵子;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;Hiderou Yoshida;吉田秀郎;Hiderou Yoshida;Hiderou Yoshida;Yukako Oda;Satomi Nadanaka;Satomi Nadanaka;Satomi Nadanaka;吉田秀郎;吉田秀郎;Hiderou Yoshida;吉田秀郎;灘中里美;灘中里美;灘中里美;吉田秀郎;小田裕香子;Z.Huang;吉田秀郎
• 通讯作者: 吉田秀郎

Role of disulfide bridges formed in the lumenal domain of ATF6 in sensing endoplasmic reticulum stress.

ATF6 腔域中形成的二硫桥在感知内质网应激中的作用。

• 发表时间: 2006
• 期刊: Molecular and Cellular Biology 27
• 作者: 神山 勉;吉村恵子;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;倭 剛久;倭 剛久;倭 剛久;Hiderou Yoshida;Hiderou Yoshida;Hiderou Yoshida;吉田秀郎;Hiderou Yoshida;Hiderou Yoshida;Yukako Oda;Satomi Nadanaka
• 通讯作者: Satomi Nadanaka