Journal
JOURNAL OF CELL SCIENCE
Volume 135, Issue 10, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.259513
Keywords
Activity-based probe; Serine hydrolase; TPP; Senescence; Benzylphosphonofluoridate
Categories
Funding
- Ministry of Science and Technology [MOST 107-3017-F-002-002, 109-2311-B-002-014-MY3, MOST 1022113-M-002-004-MY3, 105-2113-M-002-006]
- Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan
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This study reveals a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. The enzyme activity of TPPII is reduced in senescent cells, and this reduction is caused by elevated levels of the serine protease inhibitor serpinB2. In response to TPPII suppression, lysosomal biogenesis is induced to compensate for the decrease in TPPII activity.
Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immunesenescence, 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 although 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 the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and beta-galactosidase activities, suggesting that 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 levels 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. This article has an associated First Person interview with the first author of the paper.
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