Uap1-KO Mouse

Uap1, also known as UDP-N-acetylglucosamine pyrophosphorylase 1, is a metabolic enzyme. It catalyzes the last step in the eukaryotic biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), converting UTP and GlcNAc-1P to the sugar nucleotide [6]. Uap1 is involved in multiple biological processes and pathways, including the hexosamine biosynthetic pathway, and is important for N-linked glycosylation occurring in the endoplasmic reticulum [2].

Uap1 deficiency significantly impairs the activation of both DNA-and RNA-viruse-induced type I IFN pathways, and Uap1-deficient mice are highly susceptible to lethal viral infection, demonstrating its role in antiviral responses [1]. In rice, functional inactivation of Uap1 induces defense response-related lesion-mimic spots, early leaf senescence, and activates defense responses, suggesting its role in regulating leaf senescence and defense responses in plants [4,7]. In cancer research, Uap1 is overexpressed in prostate cancer and protects cancer cells from ER stress, conferring a growth advantage [2]. In lung adenocarcinoma, Uap1 is upregulated and correlated with poor clinical outcome, and could be a novel diagnostic biomarker and therapeutic target [3]. Silencing of Uap1 in bladder cancer cell lines led to reduction in proliferation, invasion, colony formation and migration capability, revealing it as a promising therapeutic target for bladder cancer [5].

In conclusion, Uap1 plays essential roles in various biological processes, including innate immune response, plant leaf development, and cancer cell survival. Studies using gene-knockout models, such as Uap1-deficient mice and rice mutants, have significantly contributed to understanding its functions in antiviral responses, leaf senescence, and cancer-related processes, providing insights into potential therapeutic targets for diseases like viral infections and certain cancers.

References:

1. Yang, Shuai, Jin, Shouheng, Xian, Huifang, Li, Mengqiu, Cui, Jun. 2023. Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to facilitate innate immune response. In Molecular cell, 83, 298-313.e8. doi:10.1016/j.molcel.2022.12.007. https://pubmed.ncbi.nlm.nih.gov/36603579/

2. Itkonen, H M, Engedal, N, Babaie, E, Schlomm, T, Mills, I G. 2014. UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. In Oncogene, 34, 3744-50. doi:10.1038/onc.2014.307. https://pubmed.ncbi.nlm.nih.gov/25241896/

3. Wang, Xianghai, Chen, Xingwu, Liu, Hongbing. 2020. Expression and Bioinformatics-Based Functional Analysis of UAP1 in Lung Adenocarcinoma. In Cancer management and research, 12, 12111-12121. doi:10.2147/CMAR.S282238. https://pubmed.ncbi.nlm.nih.gov/33269005/

4. Wang, Zhaohai, Wang, Qiang, Wei, Lingxia, Zhang, Hongyu, Huang, Yingjin. 2021. UDP-N-Acetylglucosamine Pyrophosphorylase 2 (UAP2) and 1 (UAP1) Perform Synergetic Functions for Leaf Survival in Rice. In Frontiers in plant science, 12, 685102. doi:10.3389/fpls.2021.685102. https://pubmed.ncbi.nlm.nih.gov/34249055/

5. Puttamallesh, Vinuth N, Deb, Barnali, Gondkar, Kirti, Gowda, Harsha, Kumar, Prashant. 2020. Quantitative Proteomics of Urinary Bladder Cancer Cell Lines Identify UAP1 as a Potential Therapeutic Target. In Genes, 11, . doi:10.3390/genes11070763. https://pubmed.ncbi.nlm.nih.gov/32650368/

6. Raimi, Olawale G, Hurtado-Guerrero, Ramon, Borodkin, Vladimir, Ferguson, Michael A J, van Aalten, Daan M F. 2020. A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor. In RSC chemical biology, 1, 13-25. doi:10.1039/c9cb00017h. https://pubmed.ncbi.nlm.nih.gov/34458745/

7. Wang, Zhaohai, Wang, Ya, Hong, Xiao, Tang, Huiru, Li, Yangsheng. 2014. Functional inactivation of UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1) induces early leaf senescence and defence responses in rice. In Journal of experimental botany, 66, 973-87. doi:10.1093/jxb/eru456. https://pubmed.ncbi.nlm.nih.gov/25399020/