SIRT2, an NAD+-dependent deacetylase, is the only sirtuin predominantly found in the cytoplasm, yet also present in mitochondria and the nucleus. It plays crucial roles in multiple biological processes, such as mitosis regulation, genome integrity, cell differentiation, and homeostasis, with its functions associated with various pathways like cGAS-STING, Wnt/β-catenin, and AMPK-LKB1 [2,3,4,5]. Genetic models, like KO/CKO mouse models, are valuable for studying SIRT2's functions.

In KO mouse models, SIRT2 deficiency has diverse effects. In osteoporosis models, liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss by upregulating LRG1 in hepatocyte-derived sEVs, which inhibits osteoclast differentiation in BMDMs [1]. In aging-related and angiotensin II-induced pathological cardiac hypertrophy models, Sirt2 knockout exaggerates cardiac hypertrophy and fibrosis, while cardiac-specific SIRT2 overexpression protects the heart. Mechanistically, SIRT2 promotes AMPK activation by deacetylating LKB1 [4]. In hypertensive nephropathy models, Sirt2-deficient mice show exacerbated hypertensive renal injury due to hyperacetylation of septin4-K174, as SIRT2 deacetylates septin4-K174 to mitigate the injury [6]. Also, in IBD models, genetic knockout of Sirt2 aggravates symptoms, in contrast to the alleviating effect of pharmacological inhibition [7].

In conclusion, SIRT2 is essential in maintaining normal physiological functions across various tissues. Model-based research, especially KO/CKO mouse models, has revealed its significance in diseases such as osteoporosis, cardiac hypertrophy, hypertensive nephropathy, and IBD. Understanding SIRT2's functions provides potential therapeutic targets for these diseases.

References:

1. Lin, Longshuai, Guo, Zengya, He, Enjun, He, Ming, Zhao, Qinghua. 2023. SIRT2 regulates extracellular vesicle-mediated liver-bone communication. In Nature metabolism, 5, 821-841. doi:10.1038/s42255-023-00803-0. https://pubmed.ncbi.nlm.nih.gov/37188819/

2. Wang, Yan, Yang, Jingqi, Hong, Tingting, Chen, Xiongjin, Cui, Lili. 2019. SIRT2: Controversy and multiple roles in disease and physiology. In Ageing research reviews, 55, 100961. doi:10.1016/j.arr.2019.100961. https://pubmed.ncbi.nlm.nih.gov/31505260/

3. Li, Yutong, Bie, Juntao, Song, Chen, You, Fuping, Luo, Jianyuan. 2023. SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1. In EMBO reports, 24, e57500. doi:10.15252/embr.202357500. https://pubmed.ncbi.nlm.nih.gov/37870259/

4. Tang, Xiaoqiang, Chen, Xiao-Feng, Wang, Nan-Yu, Liu, De-Pei, Chen, Hou-Zao. 2017. SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy. In Circulation, 136, 2051-2067. doi:10.1161/CIRCULATIONAHA.117.028728. https://pubmed.ncbi.nlm.nih.gov/28947430/

5. Li, Chang, Zhou, Yuning, Rychahou, Piotr, Wang, Qingding, Evers, B Mark. 2020. SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation. In Cellular and molecular gastroenterology and hepatology, 10, 43-57. doi:10.1016/j.jcmgh.2020.01.004. https://pubmed.ncbi.nlm.nih.gov/31954883/

6. Zhang, Ying, Zhang, Naijin, Zou, Yuanming, Cao, Liu, Sun, Yingxian. 2023. Deacetylation of Septin4 by SIRT2 (Silent Mating Type Information Regulation 2 Homolog-2) Mitigates Damaging of Hypertensive Nephropathy. In Circulation research, 132, 601-624. doi:10.1161/CIRCRESAHA.122.321591. https://pubmed.ncbi.nlm.nih.gov/36786216/

7. Hou, Dan, Yu, Tao, Lu, Xuan, Ho, Thanh Tu, Lin, Hening. 2024. Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2319833121. doi:10.1073/pnas.2319833121. https://pubmed.ncbi.nlm.nih.gov/38648480/