期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms21103720
关键词
DNA damage; extracellular vesicle (EV); exosome; ceramide pathway; cellular senescence; senescence-associated secretory phenotype (SASP); senescence-associated extracellular vesicle (SA-EV); autophagy; bacterial infection; Bacillus Calmette-Guerin (BCG)
资金
- Japan Science and Technology Agency (JST)-PRESTO [JPMJPR17H7]
- Japan Agency of Medical Research and Development (AMED) [19gm6110023h0001]
- Japan Society for the Promotion of Science (JSPS) [17K19618, 18K15073, 19H03507, 20K16163, 20K16344]
- Vehicle Racing Commemorative Foundation
- Takeda Science Foundation
- Mitsubishi Foundation
- Grants-in-Aid for Scientific Research [20K16163, 20K16344, 19H03507, 18K15073, 17K19618] Funding Source: KAKEN
DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses.
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