Heparan sulfate sulfation is critical for endocytosis of FGF receptor to prevent cellular senescence

초록

The heparan sulfate (HS) sulfation is an important post-translational modification that plays a regulatory role in cell growth, motility, and metabolism. However, relationship between HS sulfation and cellular senescence has not been determined yet. We previously demonstrated that the augmented FGF receptor (FGFR)/AKT signaling results in cellular senescence in a HS sulfation-dependent manner (Cell Death Differ. 2016. 23:417-429). In this study, we further analysis the mechanism whereby the augmented FGFR induces cellular senescence. We found that knockdown of PAPSS2, a synthetic enzyme of the general sulfur donor PAPS, induces cellular senescence through the augmented FGFR signaling occurred by blockade of FGFR endocytosis. Sodium chlorate, a specific inhibitor of PAPS synthetase, also prevents FGFR endocytosis and induces the augmented FGFR signaling, finally leading cellular senescence. These results indicate that HS critically involves in FGFR endocytosis and blockade of FGFR endocytosis results in cellular senescence due to the augmented FGFR signaling. Collectively, this study establishes a link between endocytosis and cellular senescence in a HS sulfation-dependent manner.