ZIP4

ZIP4 (ZIP = acronym for: Zrt-Irt-like protein) also known as SLC39A4, a transport protein in the human body, belongs to the family of zinc/iron-regulated transporter-like proteins (ZIP). The ZIP protein family and plays a central role in the absorption of zinc from the intestine. ZIKP4 is encoded by the SLC39A4 gene (SLC39A4 stands for "Solute Carrier Family 39 Member 4"), which is located on chromosome 8q24.3. ZIP4 consists of 8 transmembrane regions - the protein thus "crosses" the cell membrane several times. ZIP4 has a long ECD (extracellular domain) N-terminus, which probably helps in regulation (e.g. in recognizing zinc deficiency). It is likely that this histidine-rich loop functions as a metal chaperone that facilitates zinc binding to the transport site and/or as a zinc sensor that allosterically regulates the transport mechanism (Zhang T et al. 2019).

ZIKP4 is mainly located in the cells of the small intestinal mucosa. Transports zinc by passive transport (no energy consumption, follows the concentration gradient).

The body regulates the activity of ZIP4 depending on the zinc requirement. If there is a zinc deficiency, ZIP4 is increasingly brought to the cell surface; if there is an excess of zinc, it is broken down again.

The SLC39A family (Solute Carrier 39A) consists of 14 members that are thought to regulate zinc uptake into the cytoplasm. Among these, ZIP4 is known to be particularly important for zinc homeostasis (Zhang T et al. (2019). ZIP4 accumulates on the apical surface of enterocytes and endoderm cells when zinc is deficient, as the mRNA is more stable and the protein is stabilized. In contrast, when zinc is supplied, the mRNA is destabilized and the protein is internalized and rapidly degraded. Animal experiments show the importance of ZIP4 for zinc homeostasis when the coding SLC39A gene is specifically deleted. Homozygous Zip4 knockout embryos die during early morphogenesis. They exhibit a number of developmental defects, including exencephaly, anophthalmia and severe growth retardation. Mice heterozygous for Zip4 knockout are hypersensitive to zinc deficiency, suggesting that humans heterozygous for this gene may also be highly sensitive to zinc deficiency (Andrews GK 2008).

Mutations in the SLC39A gene cause the clinical picture of acrodermatitis enteropathica (AE), a rare recessive-lethal genetic disease in humans. About half of the missense mutations that cause AE occur within the large N-terminal extracellular domain (ECD).

Zinc is an essential trace element - it is required for hundreds of enzymes, the immune system, growth and wound healing (Ogawa Y et al. 2018).

ZIP4 has been shown to be involved in tumor growth, metastasis, drug tolerance and various other processes. Most studies suggest that ZIP4 regulates the malignant biological behavior of tumors via zinc ions as a secondary messenger. ZIP4 itself binds to ephrin-B1 to regulate tumor metastasis.

ZIP4 is being investigated as a potential biomarker or therapeutic approach (Guo H et al. 2024).

1. Andrews GK (2008) Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem Soc Trans 36:1242-1246.
2. Guo H et al. (2024) Research progress on the molecular structure, function, and application in tumor therapy of zinc transporter ZIP4. Int J Biol Sci 20:5910-5924.
3. Ogawa Y et al (2018) Zinc and Skin Disorders. Nutrients 10:199.
4. Zhang T et al. (2019) The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and plays a role in zinc transport. Biochem J 476:1791-1803.