Slc39a5, a zinc transporter, plays a crucial role in regulating cellular zinc homeostasis. Zinc is essential for numerous cellular functions, and Slc39a5 is involved in various biological processes and pathways, such as the TGF-β, PI3K/AKT, and NF-κB pathways, which are related to extracellular matrix synthesis, cell proliferation, and inflammation respectively [1,2,4].

In high myopia, SLC39A5 knockout (KO) human embryonic kidney cells (HEK293) showed morphogenesis and migration abnormalities, along with significant injury to extracellular matrix (ECM) constituents. RNA-seq and qRT-PCR revealed decreased transcription of ECM-related genes in KO cells. SLC39A5 depletion inhibited the TGF-β signalling, which was reversed by its re-expression. Insufficient zinc chelation due to SLC39A5 depletion destabilized Smad proteins, inhibiting TGF-β signalling and downstream ECM synthesis [1]. In lung adenocarcinoma, SLC39A5 promoted cell proliferation by accelerating the G1-to-S phase transition and inhibiting apoptosis, acting through the activation of the PI3K/AKT signalling [2]. In zebrafish, knocking down slc39a5 expression led to cardiac ischaemia, abnormal venous angiogenesis, and reduced endothelial cell proliferation and migration, indicating its role in regulating zinc homeostasis for proper venous angiogenesis [3]. In pancreatic β-cells, β-cell-specific Slc39a5 knockout mice had impaired insulin secretion, reduced glucose tolerance, and decreased expression of Pgc-1α and Glut2, suggesting Slc39a5's role in glucose sensing and insulin secretion [5]. Genetic inactivation of SLC39A5 in mice improved liver function and reduced hyperglycemia in obesity, through elevated hepatic zinc levels and activation of hepatic AMPK and AKT signalling [6].

In summary, Slc39a5 is vital for multiple biological processes including extracellular matrix synthesis, cell proliferation, angiogenesis, glucose sensing, and insulin secretion. Studies using gene knockout models, especially in mice, have provided valuable insights into its role in diseases such as high myopia, lung adenocarcinoma, and metabolic disorders, highlighting its potential as a therapeutic target in these disease areas [1,2,3,5,6].

References:

1. Dong, Shanshan, Tian, Qi, Zhu, Tengfei, Xia, Lu, Hu, Zhengmao. 2021. SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis. In Journal of cellular and molecular medicine, 25, 8432-8441. doi:10.1111/jcmm.16803. https://pubmed.ncbi.nlm.nih.gov/34302427/

2. Liu, Zhaohui, Hu, Zheng, Cai, Xingdong, Liu, Shengming. 2021. SLC39A5 promotes lung adenocarcinoma cell proliferation by activating PI3K/AKT signaling. In Pathology, research and practice, 224, 153541. doi:10.1016/j.prp.2021.153541. https://pubmed.ncbi.nlm.nih.gov/34252710/

3. Xia, Zhidan, Bi, Xinying, Lian, Jia, Min, Junxia, Wang, Fudi. 2020. Slc39a5-mediated zinc homeostasis plays an essential role in venous angiogenesis in zebrafish. In Open biology, 10, 200281. doi:10.1098/rsob.200281. https://pubmed.ncbi.nlm.nih.gov/33081634/

4. Sun, Jiani, Gan, Lei, Lv, Siji, Dai, Chaoqun, Sun, Jing. 2023. Exposure to Di-(2-Ethylhexyl) phthalate drives ovarian dysfunction by inducing granulosa cell pyroptosis via the SLC39A5/NF-κB/NLRP3 axis. In Ecotoxicology and environmental safety, 252, 114625. doi:10.1016/j.ecoenv.2023.114625. https://pubmed.ncbi.nlm.nih.gov/36774801/

5. Wang, Xinhui, Gao, Hong, Wu, Wenhui, Min, Junxia, Wang, Fudi. 2018. The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2. In Protein & cell, 10, 436-449. doi:10.1007/s13238-018-0580-1. https://pubmed.ncbi.nlm.nih.gov/30324491/

6. Chim, Shek Man, Howell, Kristen, Dronzek, John, Economides, Aris N, Nistala, Harikiran. 2024. Genetic inactivation of zinc transporter SLC39A5 improves liver function and hyperglycemia in obesogenic settings. In eLife, 12, . doi:10.7554/eLife.90419. https://pubmed.ncbi.nlm.nih.gov/39671241/