Regulation of ER stress response by cytoplasmic mRNA splicing

XBP1是调节哺乳动物内质网应激的关键转录因子。XBP1的表达主要在mRNA剪接水平上调节。响应于ER应激，XBP1前mRNA转化为成熟mRNA，从成熟mRNA翻译活性转录因子pXBP1（S）并激活ER应激反应。ER应激反应参与了包括阿尔茨海默病在内的神经退行性疾病的发生，阐明ER应激反应的机制将有助于这类疾病的预防、诊断和治疗。我们还发现，pXBP1（U），一种由未剪接的XBP1前mRNA翻译的蛋白质，是pXBP1（S）的负调节因子。这表明哺乳动物细胞在内质网应激反应中迅速地将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科普内质网应激的主要原因，该研究为内质网应激反应的研究做出了重要贡献。不仅开创了细胞质剪接这一新的研究领域，而且对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子，以阐明其分子机制。

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.