DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

Int J Mol Sci. 2020 May 25;21(10):3720. doi: 10.3390/ijms21103720.

Abstract

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.

Keywords: Bacillus Calmette–Guérin (BCG); DNA damage; autophagy; bacterial infection; cellular senescence; ceramide pathway; exosome; extracellular vesicle (EV); senescence-associated extracellular vesicle (SA-EV); senescence-associated secretory phenotype (SASP).

MeSH terms

  • Animals
  • Autophagy
  • Cell Line
  • Cells, Cultured
  • Cellular Senescence*
  • Ceramides / metabolism*
  • DNA Damage*
  • Extracellular Vesicles / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Transferases (Other Substituted Phosphate Groups) / genetics
  • Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

  • Ceramides
  • Transferases (Other Substituted Phosphate Groups)
  • Sgms2 protein, mouse
  • Smpd3 protein, mouse
  • Sphingomyelin Phosphodiesterase