Su Yuanyuan, Xu Chenzhong, Sun Zhaomeng, Liang Yao, Li Guodong, Tong Tanjun, Chen Jun
Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
Aging (Albany NY). 2019 Jan 23;11(2):549-572. doi: 10.18632/aging.101760.
Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α 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 up-regulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1α level, NF-κB activity and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu level is elevated during cellular senescence. Lowering Cu level decreases cell surface-bound IL-1α level, NF-κB 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-1α delays cellular senescence. In addition, intervention of S100A13 affects multiple SASP and cellular senescence mediators including p38, γ-H2AX, and mTORC1. Taken together, our findings unveil a critical role of the non-classical secretory pathway of IL-1α in cellular senescence and SASP regulation.
衰老细胞表现出衰老相关分泌表型（SASP），其在癌症、衰老等过程中发挥重要作用。细胞表面结合的白细胞介素-1α（IL-1α）是一种关键的SASP因子，作为上游调节因子诱导核因子κB（NF-κB）活性及随后的SASP基因转录。IL-1α通过S100A13蛋白依赖性非经典分泌途径输出到细胞表面。然而，该分泌途径在细胞衰老过程中的状态及其在细胞衰老中的作用仍不清楚。在此，我们表明S100A13在各种类型的细胞衰老中上调。S100A13过表达增加细胞表面相关的IL-1α水平、NF-κB活性及随后多个SASP基因的诱导，而S100A13敲低则起相反作用。我们还发现细胞衰老过程中铜水平升高。降低铜水平会降低细胞表面结合的IL-1α水平、NF-κB活性和SASP产生。此外，S100A13过表达促进癌基因Ras诱导的细胞衰老（Ras OIS）、阿霉素诱导的癌细胞衰老（TIS）和复制性衰老，而IL-1α非经典分泌途径的损伤会延迟细胞衰老。此外，对S100A13的干预会影响多种SASP和细胞衰老介质，包括p38、γ-H2AX和哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）。综上所述，我们的研究结果揭示了IL-1α非经典分泌途径在细胞衰老和SASP调节中的关键作用。
