Project for Cellular Senescence, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Graduate School of Science and Engineering, Ibaraki University, Mito, Ibaraki 310-8512, Japan.
Int J Mol Sci. 2020 May 25;21(10):3720. doi: 10.3390/ijms21103720.
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.
DNA 损伤可由各种致癌应激引起，作为一种重要的肿瘤抑制机制，可诱导细胞死亡或细胞衰老。衰老细胞表现出衰老相关分泌表型（SASP）的特征，向周围组织分泌炎症蛋白，并促进各种与年龄相关的病理。除了这种炎症蛋白的分泌外，衰老细胞中外泌体（EV）的释放也被上调。然而，这一现象背后的分子机制尚不清楚。在这里，我们表明 DNA 损伤通过下调鞘磷脂合酶 2（SMS2）和上调中性鞘磷脂酶 2（nSMase2）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，通过去除源自染色体 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，这条 SA-EV 途径可能在细胞稳态中发挥重要作用，尤其是在衰老细胞中。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。
