Regulation of ER stress response by cytoplasmic mRNA splicing

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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.