Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death

Abstract

Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis. This research investigates the function of a protein, CREB3, in regulated cell death (RCD-a process vital for cell health and disease prevention). The scientists discovered that CREB3 is found in the cell's nuclear membrane (a barrier protecting the cell's nucleus) and interacts with DNA. When this protein is split, it can cause the nuclear membrane to break, leading to a type of cell death known as karyoptosis. This process is different from other cell death types like apoptosis and autophagy. The research also found that certain stress factors, such as ultraviolet B radiation and endoplasmic reticulum stress (stress in a cell component that makes proteins), can initiate this process. The results imply that focusing on CREB3 could be a potential cancer treatment strategy. More research is required to further understand these results. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.