Tgm2-Catalyzed Covalent Cross-Linking of IκBα Drives NF-κB Nuclear Translocation to Promote SASP in Senescent Microglia.

1. Aging Cell. 2025 May;24(5):e14463. doi: 10.1111/acel.14463. Epub 2025 Jan 3. Tgm2-Catalyzed Covalent Cross-Linking of IκBα Drives NF-κB Nuclear Translocation to Promote SASP in Senescent Microglia. Li Z(1), Wang T(1), Du S(1), Miao Z(1), Zhao Y(1), Tang Y(1), Meng X(1), Yu S(1), Zhang D(1), Jiang H(1), Du K(1), Wei W(2), Deng H(1). Author information: (1)MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China. (2)Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China. Microglia, as resident immune cells in the central nervous system (CNS), play a crucial role in maintaining homeostasis and phagocytosing metabolic waste in the brain. Senescent microglia exhibit decreased phagocytic capacity and increased neuroinflammation through senescence-associated secretory phenotype (SASP). This process contributes to the development of various neurodegenerative diseases, including Alzheimer's disease (AD). In this study, we found that SASP was elevated in senescent microglia, and proteomics showed that Tgm2 was upregulated. Mechanistically, we revealed that Tgm2-catalyzed covalent cross-linking of IκBα at K22 and Q248 residues in the cytoplasm of microglia, resulting in the reduction of IκBα and nuclear translocation of NF-κB to promote SASP production. Treatment of senescent microglia with Tgm2 inhibitors (Tg2-IN1 and Cys-D) resulted in reduced NF-κB nuclear translocation and decreased SASP. Additionally, oral administration of Cys-D significantly improved the aging phenotype in aged mice. To summarize, Tgm2 is a potential target for antiaging, and inhibitors of Tgm2 can serve as novel prophylactics or senomorphics. © 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. DOI: 10.1111/acel.14463 PMCID: PMC12073898 PMID: 39749582 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no conflicts interest.