Isx, short for intestine-specific homeobox, is an intestine-specific transcription factor. It participates in maintaining vitamin A metabolism by regulating the expression of beta-carotene 15,15'-monooxygenase (Bcmo1), which is involved in vitamin A synthesis [4]. Isx may also play a role in genetic regulation related to carotenoid metabolism, as genetic deletion of Isx can affect zeaxanthin accumulation in tissues [5].

In a transgenic mice model, the HCV core protein-Isx axis enhances metabolic disturbance (especially in lipid and glucose metabolism) and immune suppression, finally leading to chronic liver fibrosis in a high-fat diet-induced disease model. Cells with specific ISX shRNAi inhibit HCV core protein-induced metabolic disturbance and immune suppression, highlighting the significance of this axis in HCV-induced chronic liver disease [2]. Also, in lung cancer, PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition (EMT), and the ectopic expression of PCAF-ISX-BRD4 axis components correlates with clinical metastatic features and poor prognosis [1,3].

In conclusion, Isx is crucial for maintaining vitamin A metabolism and carotenoid metabolism. Mouse models have revealed its role in diseases such as HCV-induced chronic liver disease and lung cancer metastasis. Understanding Isx's functions can potentially provide new insights for treating these diseases.

References:

1. Wang, Li-Ting, Liu, Kwei-Yan, Jeng, Wen-Yih, Huang, Shau-Ku, Hsu, Shih-Hsien. 2020. PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition. In EMBO reports, 21, e48795. doi:10.15252/embr.201948795. https://pubmed.ncbi.nlm.nih.gov/31908141/

2. Wang, Li-Ting, Wang, Shen-Nien, Chiou, Shyh-Shin, Huang, Shau-Ku, Hsu, Shih-Hsien. 2023. HCV Core Protein-ISX Axis Promotes Chronic Liver Disease Progression via Metabolic Remodeling and Immune Suppression. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2300644. doi:10.1002/advs.202300644. https://pubmed.ncbi.nlm.nih.gov/37316966/

3. Stemmler, Marc P. 2020. PCAF, ISX, and BRD4: a maleficent alliance serving lung cancer malignancy. In EMBO reports, 21, e49766. doi:10.15252/embr.201949766. https://pubmed.ncbi.nlm.nih.gov/31908099/

4. Seino, Yusuke, Miki, Takashi, Kiyonari, Hiroshi, Iwanaga, Toshihiko, Seino, Susumu. 2007. Isx participates in the maintenance of vitamin A metabolism by regulation of beta-carotene 15,15'-monooxygenase (Bcmo1) expression. In The Journal of biological chemistry, 283, 4905-11. doi:. https://pubmed.ncbi.nlm.nih.gov/18093975/

5. Thomas, Linda D, Ramkumar, Srinivasagan, Golczak, Marcin, von Lintig, Johannes. 2023. Genetic deletion of Bco2 and Isx establishes a golden mouse model for carotenoid research. In Molecular metabolism, 73, 101742. doi:10.1016/j.molmet.2023.101742. https://pubmed.ncbi.nlm.nih.gov/37225015/