DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses
DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses
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DOI：
10.3390/ijms21103720
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Takahashi, Akiko
中科院分区：
文献类型：
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作者：
Hitomi, Kazuhiro;Okada, Ryo;Takahashi, Akiko
由各种致癌应激引起的DNA损伤可诱导细胞死亡或细胞衰老，这是一种重要的肿瘤抑制机制。衰老细胞呈现衰老相关分泌表型（SASP）的特征，向周围组织分泌炎性蛋白，并导致各种与年龄相关的疾病。除了这种炎性蛋白的分泌，衰老细胞中细胞外囊泡（EVs）的释放也上调。然而，这种现象背后的分子机制仍不清楚。在此，我们表明DNA损伤通过鞘磷脂合成酶2（SMS2）的下调和中性鞘磷脂酶2（nSMase2）的上调激活神经酰胺合成途径，导致衰老相关EV（SA - EV）生物发生增加。EV生物发生途径与自噬介导的降解途径一起，通过清除来自染色体DNA或细菌感染的细胞质DNA片段来阻止细胞凋亡。我们的数据表明，这种SA - EV途径可能在细胞内稳态中发挥重要作用，特别是在衰老细胞中。总之，DNA损伤通过激活神经酰胺途径引发SA - EV释放，以保护细胞免受过度的炎症反应。
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.