Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death
0
조회
0
다운로드
0
인용
0
참고문헌
초록
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.
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.
참고문헌 (45)
- Galluzzi, L., "Molecular mechanisms of cell death : recommendations of the Nomenclature Committee on Cell Death 2018", Cell Death Differ, 25, pp.486~541 (2018)
- Darzynkiewicz, Z., "Cytometry in cell necrobiology : analysis of apoptosis and accidental cell death(necrosis)", Cytometry, 27, pp.1~20 (1997)
- Zamzami, N., "Mitochondrial implication in accidental and programmed cell death: apoptosis and necrosis", J. Bioenerg. Biomembr, 29, pp.185~193 (1997)
- Fairlie, W. D., "Crosstalk between apoptosis and autophagy signaling pathways", Int. Rev. Cell Mol. Biol, 352, pp.115~158 (2020)
- Yang, Y., "Targeting regulated cell death with plant natural compounds for cancer therapy : a revisited review of apoptosis, autophagy-dependent cell death, and necroptosis", Phytother. Res, 37, pp.1488~1525 (2023)
- Chen, D. Q., "Small molecules as modulators of regulated cell death against ischemia", reperfusion injury, 2022, pp.42, 2067~2101
- Newton, K., "Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis", Nature, 574, pp.428~431 (2019)
- Peng, F., "Regulated cell death(RCD)in cancer : key pathways and targeted therapies", Signal. Transduct. Target Ther, 7, pp.286~ (2022)
- Wu, J., "Targeting regulated cell death with phar macological small molecules : an update on autophagy-dependent cell death, ferroptosis, and necroptosis in cancer", J. Med Chem, 65, pp.2989~3001 (2022)
- Woo, Y., "Regulated necrotic cell death in alternative tumor therapeutic strategies", Cells, 9 (2020)[DOI]
- Qin, R., "Naturally derived indole alkaloids targeting regulated cell death(RCD)for cancer therapy : from molecular mechanisms to potential therapeutic targets", J. Hematol. Oncol, 15, pp.133~ (2022)
- Baron, O., "Karyoptosis : a novel type of cell death caused by chronic autophagy inhibition", Autophagy, 14, pp.722~723 (2018)
- Napoletano, F., "Intersections between regulated cell death and autophagy", Trends Cell Biol, 29, pp.323~338 (2019)
- Versaevel, M., "Cell conflinement : putting the squeeze on the nucleus", Soft Matter, 9, pp.6665~ (2013)
- Liang, G., "Luman", CREB3 induces transcription of the endoplasmic reticulum(ER)stress response protein Herp through an ER stress response element, 2006, pp.26, 7999~8010
- Howley, B. V., "A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer", Oncogene, 37, pp.1308~1325 (2018)
- Hetz, C., "The unfolded protein response and cell fate control", Mol. Cell, 69, pp.169~181 (2018)
- Reiling, J. H., "A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens", Nat. Cell Biol, 15, pp.1473~1485 (2013)
- Kang, H., "Human leucine zipper protein sLZIP induces migration and invasion of cervical cancer cells via expression of matrix metalloproteinase-9", J. Biol. Chem, 286, pp.42072~42081 (2011)
- Eleveld-Trancikova, D., "DC-STAMP interacts with ER-resident transcription factor LUMAN which becomes activated during DC maturation", Mol. Immunol, 47, pp.1963~1973 (2010)
- Martyn, A. C., "Luman", CREB3 recruitment factor regulates glucocorticoid receptor activity and is essential for prolactin-mediated maternal instinct, 2012, pp.32, 5140~5150
- Sohn, M., "Correlation of dynamic membrane f luctuations in red blood cells with diabetes mellitus and cardiovascular risks", Sci. Rep, 11, pp.7007~ (2021)
- Raggo, C., "Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis", Mol. Cell Biol, 22, pp.5639~5649 (2002)
- Audas, T. E., "A novel protein, Luman", CREB3 recruitment factor, inhibits Luman activation of the unfolded protein response, 2008, pp.28, 3952~3966
- Kim, J., "A novel PPARgamma2 modulator sLZIP controls the balance between adipogenesis and osteogenesis during mesenchymal stem cell differ entiation", Cell Death Differ, 21, pp.1642~1655 (2014)
- Kamikawa, Y., "OASIS", CREB3L1 is a factor that responds to nuclear envelope stress, 2021, pp.7, 152~
- Taimen, P., "A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization", Proc. Natl. Acad. Sci. USA, 106, pp.20788~20793 (2009)
- Cho, Y. Y., "The p53 protein is a novel substrate of ribosomal S6 kinase 2 and a critical intermediary for ribosomal S6 kinase 2 and histone H3 interaction", Cancer Res, 65, pp.3596~3603 (2005)
- Lu, C., "Cell apoptosis : requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3", Mol. Cell, 23, pp.121~132 (2006)
- Hetzer, M. W., "The nuclear envelope", Cold Spring Harb. Perspect. Biol, 2, pp.a000539~a000539 (2010)
- Seelbinder, B., "Nuclear deformation guides chromatin reorganization in cardiac development and disease", Nat. Biomed. Eng, 5, pp.1500~1516 (2021)
- Schirmer, E. C., "Nuclear membrane proteins with potential disease links found by subtractive proteomics", Science, 301, pp.1380~1382 (2003)
- Cho, Y. Y., "RSK2 as a key regulator in human skin cancer", Carcinogenesis, 33, pp.2529~2537 (2012)
- Wang, M. L., "Andrographolide sodium bisulfate attenuates UV‑induced photo‑damage by activating the keap1", Nrf2 pathway and downregulating the NF‑kappaB pathway in HaCaT keratinocytes, 2020, pp.45, 343~352
- Arul, N., "A rising cancer prevention target of RSK2 in human skin cancer", Front. Oncol, 3, pp.201~ (2013)
- Maeda, T., "Role of p21(Waf-1)in regulating the G1 and G2", M checkpoints in ultraviolet-irradiated keratinocytes, 2002, pp.119, 513~521
- Narayanan, D. L., "Ultraviolet radiation and skin cancer", Int. J. Dermatol, 49, pp.978~986 (2010)
- Takeuchi, H., "Longwave UV light induces the aging-associated progerin", J. Invest. Dermatol, 133, pp.1857~1862 (2013)
- Wang, A. S., "Biomarkers of cellular senescence and skin aging", Front. Genet, 9, pp.247~ (2018)
- Song, J. H., "Magnolin targeting of ERK1", 2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells, 2019, pp.58, 88~101
- Caricchio, R., "Ultraviolet B radiation-induced cell death : critical role of ultraviolet dose in inflammation and lupus autoantigen redis tribution", J. Immunol, 171, pp.5778~5786 (2003)
- Casterton, R., "Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress", Res. Sq (2023)[DOI]
- Lee, G. E., "Molecular mechanisms for the regulation of nuclear membrane integrity", Int J. Mol. Sci, 24, pp.15497~ (2023)
- Francois, F., "CREB is cleaved by caspases during neural cell apoptosis", FEBS Lett, 486, pp.281~284 (2000)
- Lee, C. J., "RSK2-induced stress tolerance enhances cell survival signals mediated by inhibition of GSK3beta activity", Biochem. Biophys. Res. Commun, 440, pp.112~118 (2013)