SIRT2, a member of the sirtuin family, is an NAD+-dependent deacetylase. It is predominantly cytoplasmic but also present in mitochondria and the nucleus. SIRT2 is involved in multiple biological processes such as cell differentiation, homeostasis, aging, and immunity, regulating pathways like cGAS-STING, Wnt/β-catenin, and AMPK signaling [2,3,5,4]. Genetic models, especially knockout (KO) mouse models, have been crucial in understanding its functions.

In KO mouse models, liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in osteoporosis models, revealing its role in liver-bone crosstalk through extracellular vesicle-mediated LRG1 transfer [1]. In aged and angiotensin II-induced pathological cardiac hypertrophy models, Sirt2 knockout exaggerates cardiac hypertrophy and fibrosis, while cardiac-specific SIRT2 overexpression protects the heart, highlighting its cardioprotective role via LKB1-AMPK signaling [4]. In SIRT2-deficient mice, there are impairments in intestinal cell proliferation and differentiation, with altered Wnt/β-catenin signaling [5]. Also, Sirt2-deficient mice show exacerbated hypertensive renal injury due to hyperacetylation of septin4-K174, indicating SIRT2's role in hypertensive nephropathy [6].

In summary, SIRT2 plays essential roles in multiple biological processes including bone metabolism, cardiac function, intestinal cell regulation, and renal protection. Studies using SIRT2 KO mouse models have significantly advanced our understanding of its functions in osteoporosis, cardiac hypertrophy, inflammatory bowel disease, and hypertensive nephropathy, providing 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/