PEX5 integrates p38 MAPK signaling pathway and taurine metabolism to regulate cellular senescence in lung fibroblasts

Chronic lung diseases significantly impact the aging population globally, but their etiology is largely unknown, and the therapeutic options are minimal. Cellular senescence has been increasingly recognized as an essential driving mechanism for chronic lung diseases. Remodeling in subcellular compartments is commonly observed in senescent cells, which reciprocally regulates the senescent progression. Roles of peroxisomes in cellular senescence have been documented, but the molecular mechanisms for this regulation remain poorly understood. Here, we showed that the peroxisome pathway and the shuttling receptor PEX5 are downregulated during replicative and oxidative senescence in human fetal lung fibroblast 1 (HFL-1) cells. PEX5 knockdown can induce senescence via transcriptional suppression of LAMP1 and autophagic flux. Further study revealed that activation of the p38 MAPK signaling pathway and subsequent nuclear localization of transcription factor EB (TFEB) are the significant retrograde signals contributing to the PEX5 regulation of cellular senescence. Metabolomics analysis identified a substantial increase in taurine levels in cells with PEX5 overexpression. Reciprocally, treatment of cells with taurine enhanced PEX5 levels in the senescent HFL-1 cells and the lungs of aged mice and alleviated senescence, suggesting the presence of a taurine-dependent response in PEX5 regulation of cellular senescence. Collectively, our findings provided new insights into the peroxisomal regulation of cellular senescence by integrating the p38 MAPK retrograde signaling pathway and taurine metabolism, which may help develop anti-aging strategies to treat chronic lung diseases. Overall design: To investigate the impact of the shuttling receptor PEX5 for peroxisomes on gene expression in lung fibroblasts, cells were transduced with lentivirus supernatants of Flag, PEX5, shNC, shPEX5-1 or shPEX5-2 for 24 hours. 3 days post-infection, gene expression profiling was conducted using RNA-seq data obtained from three independent replicates.