Dataset Information

SerpinB2/TPPII regulates senescence

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Disease Free

SUBMITTER: Yi-Ju Chen

LAB HEAD: Yi-Ju Chen

PROVIDER: PXD033808 | Pride | 2022-05-31

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	YJC_NTUH_151125_23_B2C.mgf	Mgf
	YJC_NTUH_151125_23_B2C.mzML	Mzml
	YJC_NTUH_151125_23_B2C.mzid.gz	Mzid
	YJC_NTUH_151125_23_B2C.raw	Raw
	YJC_NTUH_151125_23_DMSO.mgf	Mgf

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Publications

Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.

Liao Chia-Li CL Hu Rong-Chi RC Liao Min-Shiang MS Chen Yi-Ju YJ Chen Ya-Ping YP Hsieh Hsi-Hsien HH Tai Chih-Hsuan CH Chou Tzyy-Chao TC Chu Chi-Yuan CY Chen Yu-Ju YJ Lo Lee-Chiang LC Lin Jing-Jer JJ

Journal of cell science 20220525 10

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 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 although the mRNA and protein levels of TPPII were not altered during senescence, its enzymat ...[more]

PMID: 35466366

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Project description:BACKGROUND: Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.METHODS: We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.RESULTS: Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. CONCLUSION: In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.