Nuclear envelope damage preferentially triggers CREB3 cleavage to induce abnormal nuclear morphology = 핵막 손상에 의한 CREB3 의 절단과 핵 형태변화 기전에 관한 연구

다국어 초록 (Multilingual Abstract)

The nuclear envelope （NE） is not merely a physical barrier separating genomic DNA from the cytoplasm but functions as a mechanosensory platform that regulates chromatin organization and gene expression through the nuclear lamina and linker of nucleoskeleton and cytoskeleton （LINC） complex. Dysfunction of NE components leads to abnormal nuclear morphology, genomic instability, and cellular senescence, and is linked to human diseases including laminopathies, muscular dystrophy, neurodegenerative disorders, and cancer. Recent studies demonstrated that cyclic AMP-responsive element-binding protein 3 （CREB3）, previously characterized as an endoplasmic reticulum （ER）/Golgi-bound transcription factor, directly localizes to the inner nuclear membrane （INM） and maintains NE structural homeostasis through its association with lamins and chromatin DNA. Furthermore, aberrant accumulation of the cleaved form of CREB3 （CREB3-CF） has been shown to induce karyoptosis, a regulated cell death characterized by nuclear lobulation, chromatin herniation, and NE rupture. However, the conditions that trigger full-length CREB3 （CREB3-FL） cleavage and the mechanisms through which karyoptosis proceeds have not yet been identified. Our research demonstrated that NE damage preferentially triggers CREB3-FL cleavage to induce karyoptosis. Paclitaxel, which causes NE damage through cytoskeletal imbalance, selectively induced CREB3-FL cleavage, whereas the DNA-damaging agent etoposide did not. This cleavage was accompanied by p53-independent increases in Ser139-phosphorylated histone H2AX （γH2AX） and p21, consistent with the biochemical signature of karyoptosis. Ectopic expression of CREB3-CF further triggered cleavage of endogenous CREB3-FL, resulting in NE rupture, aberrant nuclear morphology, and karyoptotic cell death. CREB3-depleted cells showed enhanced NE damage under ER stress, supporting a model in which CREB3-FL actively maintains NE structural stability at the INM. Proteomic analysis further revealed that CREB3-CF overexpression upregulated actomyosin-related proteins while downregulating LINC complex and lamin proteins, suggesting that CREB3-CF contributes to NE remodeling as a transcription factor beyond competitive inhibition of CREB3-FL alone. Altogether, this study demonstrates that NE damage functions as an upstream stress signal that preferentially induces CREB3-FL cleavage independently of canonical DNA damage responses （DDR）. The sequential process in which NE damage triggers CREB3-FL cleavage and the resulting CREB3-CF remodels NE architecture positions CREB3 as a potential mechanosensor at the INM. This cytoskeleton–NE–CREB3 signaling axis might offer a molecular framework for understanding NE-associated pathologies and for developing therapeutic strategies that exploit karyoptosis.

목차 (Table of Contents)

• Ⅰ. INTRODUCTION 1
• II. MATERIALS AND METHODS 18
• III. RESULTS 27
• IⅤ. DISCUSSION 48
• Ⅴ. CONCLUSION 56
• ⅤI. REFERENCES 58
• ⅤII. 국문 초록 62