Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKα dependent manner

Oxidative stress induces not only senescence but also autophagy in a variety of mammalian cells. However, the relationship between these two has not been well established and thus, was investigated in the present study using WI38 human diploid fibroblasts (WI38 cells) as a model system. Our results showed that exposure of WI38 cells to H2O2 induced both senescence and autophagy. Downregulation of autophagy protein 5 (Atg5) with Atg5 siRNA inhibited not only autophagy but also senescence induced by H2O2. Further studies showed that Atg5 regulates H2O2-induced senescence primarily by up-regulating the expression of p21 at the level of post-transcription. In addition, we examined the mechanisms by which H2O2 induces autophagy in WI38 cells. Our results revealed that H2O2 increases autophagy independent of the mammalian target of rapamycin (mTOR) negative feedback pathway. Instead, the induction of autophagy by H2O2 depends on the induction of intracellular production of reactive oxygen species (ROS) and activation of the p38 mitogen-activated protein kinase α (p38 MAPKα) pathway.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We found ROS specifically regulates autophagy to induce senescence. ► Autophagy induces senescence through p21. ► ROS activated autohpagy is not dependent on mTOR like OIS. ► ROS increases autophagy through upregulating Ulk3 and Beclin-1 transcriptionally. ► The phosphorylated p38 MAPKα links ROS and Atg (Ulk3 and Beclin-1) upregulation.