Transglutaminase 2-mediated glutamine deamidation enhances p21 stability during senescence

• 成果类型: Article
• 署名作者: Liao, Yi-Wen; Hsieh, Hsi-Hsien; Yeh, Jin-Wei; Wang, Hsin-Chiao; Huang, Shang-Yi; Wang, Pei-Yu; Lin, Jing-Jer
• 署名单位: National Taiwan University; National Taiwan University; National Taiwan University; National Taiwan University Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14282
• DOI: 10.1073/pnas.2419762122
• 发表日期: 2025-06-17
• 关键词: plasminogen-activator inhibitor; cellular senescence; tissue transglutaminase; expression; cells; interleukin-1; type-2

摘要

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 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 into the role of TGM2- mediated enzymatic deamidation in senescence and its potential relevance to age- associated conditions.