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转谷氨酰胺酶2催化的IκBα共价交联驱动核因子κB核转位，以促进衰老小胶质细胞中的衰老相关分泌表型。

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

作者信息

Li Zhiqiang, Wang Tianxiang, Du Sijing, Miao Zelong, Zhao Yujiao, Tang Yuxiang, Meng Xianbin, Yu Shangcheng, Zhang Dongyuan, Jiang Hao, Du Kunlin, Wei Wei, Deng Haiteng

机构信息

MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China.

Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.

出版信息

Aging Cell. 2025 May;24(5):e14463. doi: 10.1111/acel.14463. Epub 2025 Jan 3.

DOI:10.1111/acel.14463
PMID:39749582
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12073898/
Abstract

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.

摘要

小胶质细胞作为中枢神经系统（CNS）中的常驻免疫细胞，在维持大脑内环境稳定和吞噬代谢废物方面发挥着关键作用。衰老的小胶质细胞通过衰老相关分泌表型（SASP）表现出吞噬能力下降和神经炎症增加。这一过程促进了包括阿尔茨海默病（AD）在内的各种神经退行性疾病的发展。在本研究中，我们发现衰老小胶质细胞中SASP升高，蛋白质组学显示Tgm2上调。从机制上讲，我们揭示了Tgm2催化小胶质细胞胞质中IκBα在K22和Q248残基处的共价交联，导致IκBα减少和NF-κB核转位，从而促进SASP产生。用Tgm2抑制剂（Tg2-IN1和Cys-D）处理衰老小胶质细胞可导致NF-κB核转位减少和SASP降低。此外，口服Cys-D可显著改善老年小鼠的衰老表型。总之，Tgm2是抗衰老的潜在靶点，Tgm2抑制剂可作为新型预防药物或衰老调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/c368c8be9586/ACEL-24-e14463-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/c4eec09d4462/ACEL-24-e14463-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/4c1d08cf8cf7/ACEL-24-e14463-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/0d07c6ff89ee/ACEL-24-e14463-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/7c4288fffccb/ACEL-24-e14463-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/c368c8be9586/ACEL-24-e14463-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/c4eec09d4462/ACEL-24-e14463-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/cfc31113975a/ACEL-24-e14463-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/6c6ecd00f9b5/ACEL-24-e14463-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/ca2a235b0535/ACEL-24-e14463-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/4c1d08cf8cf7/ACEL-24-e14463-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/0d07c6ff89ee/ACEL-24-e14463-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/7c4288fffccb/ACEL-24-e14463-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/553c/12073898/c368c8be9586/ACEL-24-e14463-g005.jpg

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