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Exp. Mol. Med., 13 March 2024 | https://doi.org/10.1038/s12276-024-01195-1 Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death

Ga-Eun Lee ^1,2, Geul Bang ³, Jiin Byun ^1,2, Cheol-Jung Lee ^1,4, Weidong Chen ^1,2, Dohyun Jeung ^1,2, Hyun-Jung An ¹, Han Chang Kang ^1,2, Joo Young Lee ^1,2, Hye Suk Lee ^1,2, Young-Soo Hong ⁵, Dae Joon Kim ⁶, Megan Keniry⁷, Jin Young Kim ³, Jin-Sung Choi ¹, Manolis Fanto ⁸, Sung-Jun Cho ⁹, Kwang-Dong Kim ¹⁰ and Yong-Yeon Cho ^1,2,*

¹College of Pharmacy, The Catholic University of Korea, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
²BK21-4th, and RCD Control∙Material Research Institute, College of Pharmacy, The Catholic University of Korea, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
³Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, Cheongju-si, Chungbuk 28119, Republic of Korea.
⁴Research Center for Materials Analysis, Korea Basic Science Institute, Daejeon 34133, Republic of Korea.
⁵Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si, Chungbuk 28116, Republic of Korea.
⁶Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78504, USA.
⁷Department of Biology, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA.
⁸Department of Basic and Clinical Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
⁹University of Minnesota, Department of Medicine, 420 Delaware St SE, MMC 284, Minneapolis, MN 55455, USA.
¹⁰Division of Applied Life Science (BK21 four), PMBBRC, Gyeongsang National University, Jinju 52828, Korea.

^*Corresponding author: correspondence to Yong-Yeon Cho

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.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-21)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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