Kat5, also known as TIP60, is a lysine acetyltransferase belonging to the MYST family of histone acetyltransferases (HATs). It plays a crucial role in various biological processes such as DNA damage repair, chromatin remodeling, and gene regulation by acetylating histones and non-histone proteins. It is involved in multiple pathways including autophagy, glycolysis, innate immune response, and the regulation of cell proliferation and metastasis [1-10].

In myocardial ischemia-reperfusion injury (MIRI) models, KAT5 was downregulated, and its overexpression inhibited NLRP3-mediated cardiomyocyte pyroptosis through modulation of the STUB1/LATS2/YAP/β-catenin axis [1]. In ATC, KAT5 promoted invasion and metastasis through C-MYC stabilization, and its inhibitor NU9056 suppressed ATC progression via the c-Myc/miR-202 pathway [2,3]. In HCC, PCK1 deficiency increased O-GlcNAcylation of KAT5, epigenetically induced TWIST1 expression, and promoted metastasis [5]. In the study of the NLRP3 inflammasome, KAT5 acetylated NLRP3 at lysine 24, and KAT5 deficiency in myeloid cells reduced NLRP3 inflammasome activation [4].

In conclusion, Kat5 is essential for a variety of biological functions, with its dysregulation contributing to multiple disease conditions including MIRI, ATC, HCC, and abnormal inflammasome activation. Mouse models and in vitro functional studies have been instrumental in revealing these roles, providing potential therapeutic targets for these diseases.

References:

1. Liu, Can, Gui, Zhongxuan, An, Cheng, Gao, Xiaotian, Ge, Shenglin. 2024. STUB1 is acetylated by KAT5 and alleviates myocardial ischemia-reperfusion injury through LATS2-YAP-β-catenin axis. In Communications biology, 7, 396. doi:10.1038/s42003-024-06086-9. https://pubmed.ncbi.nlm.nih.gov/38561411/

2. Wei, Xi, Cai, Shang, Boohaker, Rebecca J, Gao, Ming, Xu, Bo. . KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. In Endocrine-related cancer, 26, 141-151. doi:10.1530/ERC-18-0193. https://pubmed.ncbi.nlm.nih.gov/30400007/

3. Xu, Wenjing, Xie, Liwei, Yang, Yingying, Cai, Shang, Tian, Ye. 2022. KAT5 Inhibitor NU9056 Suppresses Anaplastic Thyroid Carcinoma Progression through c-Myc/miR-202 Pathway. In International journal of endocrinology, 2022, 2014568. doi:10.1155/2022/2014568. https://pubmed.ncbi.nlm.nih.gov/37342240/

4. Zhang, Yening, Luo, Ling, Xu, Xueming, Lu, Ben, Zhao, Kai. 2023. Acetylation is required for full activation of the NLRP3 inflammasome. In Nature communications, 14, 8396. doi:10.1038/s41467-023-44203-0. https://pubmed.ncbi.nlm.nih.gov/38110429/

5. Liu, Rui, Gou, Dongmei, Xiang, Jin, Wang, Kai, Tang, Ni. 2021. O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis. In Oncogene, 40, 6707-6719. doi:10.1038/s41388-021-02058-z. https://pubmed.ncbi.nlm.nih.gov/34650217/