Kat5-KO Mouse

Kat5, also known as TIP60, is a lysine acetyltransferase. It plays essential roles in various biological processes by catalyzing acetylation reactions. It is involved in DNA damage repair pathways, where it facilitates histone removal at DNA breaks, and also participates in the regulation of autophagy, innate immune response, and metabolic reprogramming [3,1,4]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In a MIRI model, KAT5 was downregulated, and its overexpression inhibited NLRP3-mediated cardiomyocyte pyroptosis, relieving MIRI through the modulation of STUB1/LATS2/YAP/β-catenin axis [2]. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus-induced death, indicating that KAT5-mediated cGAS acetylation is important for the innate immune response to DNA virus [4]. KAT5 deficiency in myeloid cells and pharmacological inhibition of its enzymatic activity reduced activation of the NLRP3 inflammasome in vitro and in vivo, revealing its role in the oligomerization and full activation of NLRP3 [5].

In conclusion, Kat5 is crucial in multiple biological processes, including DNA damage repair, autophagy, innate immunity, and inflammasome activation. Model-based research, especially using Kat5 KO/CKO mouse models, has provided insights into its functions in diseases such as myocardial ischemia-reperfusion injury, DNA virus-related diseases, and inflammasome-associated conditions, contributing to our understanding of disease mechanisms and potential therapeutic targets.

References:

1. Jia, Mengshu, Yue, Xiao, Sun, Weixia, Zhao, Yuzheng, Cheng, Xiawei. 2023. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. In Science advances, 9, eadg4993. doi:10.1126/sciadv.adg4993. https://pubmed.ncbi.nlm.nih.gov/37267363/

2. 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/

3. L Hardison, Kimberly, M Hawk, Tila, A Bouley, Renee, C Petreaca, Ruben. 2022. KAT5 histone acetyltransferase mutations in cancer cells. In microPublication biology, 2022, . doi:10.17912/micropub.biology.000676. https://pubmed.ncbi.nlm.nih.gov/36530474/

4. Song, Ze-Min, Lin, Heng, Yi, Xue-Mei, Hu, Ming-Ming, Shu, Hong-Bing. 2020. KAT5 acetylates cGAS to promote innate immune response to DNA virus. In Proceedings of the National Academy of Sciences of the United States of America, 117, 21568-21575. doi:10.1073/pnas.1922330117. https://pubmed.ncbi.nlm.nih.gov/32817552/

5. 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/