Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death.
Journal
Experimental & molecular medicine
ISSN: 2092-6413
Titre abrégé: Exp Mol Med
Pays: United States
ID NLM: 9607880
Informations de publication
Date de publication:
13 Mar 2024
13 Mar 2024
Historique:
received:
01
09
2023
accepted:
02
01
2024
revised:
17
12
2023
medline:
14
3
2024
pubmed:
14
3
2024
entrez:
14
3
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38480902
doi: 10.1038/s12276-024-01195-1
pii: 10.1038/s12276-024-01195-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Catholic University of Korea (The Catholic University of Korea)
ID : M-2023-B0002-00003
Organisme : Ministry of Science, ICT and Future Planning (MSIP)
ID : 2023R1A2C2003059
Informations de copyright
© 2024. The Author(s).
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