{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nResearch on the zinc transporter encoded by the SLC39A5 gene (commonly referred to as ZIP5) has revealed its critical role in maintaining zinc homeostasis. ZIP5 is expressed in key tissues—including the intestine, pancreas, liver, kidney, and developing epithelia—and is uniquely localized to the basolateral membranes of polarized cells. Under zinc‐replete conditions, ZIP5 is positioned to mediate zinc excretion from the body, whereas during zinc deficiency the protein is removed from the cell surface and degraded, even though its mRNA remains polysome-associated, thereby permitting rapid re‐synthesis upon zinc repletion. These dynamic expression and localization patterns distinguish ZIP5 from related transporters such as ZIP4, which is induced to enhance zinc uptake when zinc is scarce."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, ZIP5 expression is governed not only transcriptionally but also through post‐transcriptional mechanisms. Its 3′-untranslated region forms a highly stable stem-loop structure flanked by conserved microRNA seed sites, which in conjunction with specific polysome-associated proteins, act to fine-tune ZIP5 translation in a zinc-dependent manner. In addition, structural characterization of the extracellular (PrP-like) domain of ZIP5 has revealed a dimeric, globular fold with significant α-helical content, suggesting an evolutionary link to prion proteins and hinting at unique biophysical properties that may influence its cellular function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in zinc excretion, ZIP5 also contributes to specific cellular functions. In pancreatic β-cells, for instance, proper ZIP5 function is essential for adequate zinc influx, which in turn supports insulin synthesis, processing, and secretion. Moreover, recent studies have linked aberrant expression of SLC39A5/ZIP5 to oncogenic processes in lung adenocarcinoma, where overexpression correlates with enhanced cell proliferation via activation of PI3K/AKT signaling pathways. These insights underscore the potential of ZIP5 as both a critical regulator of systemic zinc balance and a promising target in metabolic and cancer-related disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fudi Wang, Byung-Eun Kim, Michael J Petris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M408361200"}], "href": "https://doi.org/10.1074/jbc.M408361200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15322118"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15322118"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jodi Dufner-Beattie, Yien-Ming Kuo, Jane Gitschier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The adaptive response to dietary zinc in mice involves the differential cellular localization and zinc regulation of the zinc transporters ZIP4 and ZIP5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M409962200"}], "href": "https://doi.org/10.1074/jbc.M409962200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15358787"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15358787"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Zhixin L Huang, Jodi Dufner-Beattie, Glen K Andrews "}, {"type": "b", "children": [{"type": "t", "text": "Expression and regulation of SLC39A family zinc transporters in the developing mouse intestine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2006.03.045"}], "href": "https://doi.org/10.1016/j.ydbio.2006.03.045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16682017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16682017"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Benjamin P Weaver, Jodi Dufner-Beattie, Taiho Kambe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1515/BC.2007.149"}], "href": "https://doi.org/10.1515/BC.2007.149"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18020946"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18020946"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jim Geiser, Robert C De Lisle, Glen K Andrews "}, {"type": "b", "children": [{"type": "t", "text": "The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0082149"}], "href": "https://doi.org/10.1371/journal.pone.0082149"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24303081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24303081"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Benjamin P Weaver, Glen K Andrews "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of zinc-responsive Slc39a5 (Zip5) translation is mediated by conserved elements in the 3'-untranslated region."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biometals (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10534-011-9508-4"}], "href": "https://doi.org/10.1007/s10534-011-9508-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22113231"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22113231"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cosmin L Pocanschi, Sepehr Ehsani, Mohadeseh Mehrabian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ZIP5 ectodomain co-localizes with PrP and may acquire a PrP-like fold that assembles into a dimer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0072446"}], "href": "https://doi.org/10.1371/journal.pone.0072446"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24039764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24039764"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xinhui Wang, Hong Gao, Wenhui Wu, et al. 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