Related Experiment Video
Updated: Jun 12, 2025
LERLIC-MS/MS for In-depth Characterization and Quantification of Glutamine and Asparagine Deamidation in Shotgun Proteomics
Published on: April 9, 2017
Transglutaminase 2-mediated glutamine deamidation enhances p21 stability during senescence
Yi-Wen Liao1, Hsi-Hsien Hsieh1, Jin-Wei Yeh2
1Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Abstract:
The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.
Insights
Cellular senescence, a key aspect of aging, involves p21 stabilization. This study shows transglutaminase 2 (TGM2) deamidation of p21 stabilizes it, halting cell proliferation. Inhibiting TGM2 delays senescence and improves aging phenotypes.
Area of Science:
- Cellular and Molecular Biology
- Aging Research
- Biochemistry
Background:
- Cellular senescence limits human cell proliferation, contributing to organismal aging.
- Telomere erosion triggers a DNA damage response (DDR) involving p53, leading to cell cycle arrest via p21.
- Serine protease inhibitor B2 (serpinB2/PAI-2) stabilizes p21 in senescent cells.
Purpose of the Study:
- To elucidate the mechanism by which serpinB2 stabilizes p21 in cellular senescence.
- To investigate the role of transglutaminase 2 (TGM2) in p21 modification and senescence.
- To assess the therapeutic potential of inhibiting TGM2 in aging models.
Main Methods:
- Investigated the interaction between serpinB2 and TGM2 in senescent cells.
- Utilized biochemical assays to analyze TGM2-mediated deamidation of p21.
- Employed pharmacological TGM2 inhibition in an accelerated aging model (CKD).
Main Results:
- Demonstrated that serpinB2 upregulation activates TGM2, which deamidates p21, stabilizing it and halting proliferation.
- Showed that inhibiting TGM2 accelerates p21 degradation, delaying senescence onset.
- Reported that pharmacological TGM2 inhibition ameliorates aging phenotypes in a CKD model.
Conclusions:
- TGM2-mediated enzymatic deamidation of p21 is a critical mechanism for stabilizing the protein and driving cellular senescence.
- Targeting TGM2 activity represents a potential therapeutic strategy for age-associated diseases, including those linked to chronic kidney disease.
Related Concept Videos
01:29Protein Folding Quality Check in the RER
02:23Abnormal Proliferation