Unveiling a novel serpinB2/tripeptidyl peptidase II signaling axis during senescence

Tripeptidyl peptidase II (TPPII) degrades N-terminal tripeptides from proteins and peptides. Studies in both human and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation, and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that while the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation of lysosomal contents as well as TPPI and -galactosidase activities, suggesting that the lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together this study discloses a critical role of the serpinB2/TPPII signaling pathway in proteostasis during senescence. Since serpinB2 level can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions.