PDI-catalyzed oxidative protein folding mediates senescence by induction of ER-derived oxidative stress

Protein homeostasis is linked with aging and aging associated diseases. Oxidative protein folding occurs in the endoplasmic reticulum (ER) and produces H2O2 as a byproduct. The role of oxidative protein folding in human stem cells aging remains unknown. Here, we succeed to knockout protein disulfide isomerase (PDI), a key oxidoreductase for catalyzing oxidative protein folding, in human embryonic stem cells (hESCs) and human mesenchymal stem cells (hMSCs). Deletion of PDI does not affect the self-renewal of hESCs but significantly delays hMSCs senescence. Mechanistically, knockout of PDI slows down the rate of oxidative protein folding and decreases the leakage of ER-derived H2O2 into the nucleus, therefore alleviating oxidative stress and the secretory-associated senescence phenotype (SASP). Among the SASP-related genes, SERPINE1 is identified as a key driver for cell senescence. These findings establish a novel link between oxidative protein folding and aging. The previously unrecognized function of PDI in regulating cell senescence provides a potential target for aging and aging-related disease intervention.