S100A13 promotes senescence-associated secretory phenotype and cellular senescence via modulation of non-classical secretion of IL-1α

Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1 alpha is a crucial SASP factor and acts as an upstream regulator to induce NF-kappa B activity and subsequent SASP genes transcription. IL-1 alpha exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown. Here, we show that S100A13 is upregulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1 alpha level, NF-kappa B activity and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu2+ level is elevated during cellular senescence. Lowering Cu2+ level decreases cell surface-bound IL-1 alpha level, NF-kappa B activity and SASP production. Moreover, S100A13 overexpression promotes oncogene Ras-induced cell senescence (Ras OIS), Doxorubicin-induced cancer cell senescence (TIS) and replicative senescence, while impairment of non-classical secretory pathway of IL-1 alpha delays cellular senescence. In addition, intervention of S100A13 affects multiple SASP and cellular senescence mediators including p38, gamma-H2AX, and mTORC1. Taken together, our findings unveil a critical role of the non-classical secretory pathway of IL-1 alpha in cellular senescence and SASP regulation.