Role of ZIP Proteins in Iron Metabolism. ZIP proteins represent a family of 14 metal-ion transport proteins. ZIP proteins were initially characterized as zinc transport proteins, but we have found that at least two ZIP family members—ZIP14 and ZIP8—can transport iron in addition to zinc (1,2). The identification of ZIP14 and ZIP8 as iron transporters is significant because, to date, only one other iron import protein has been identified (i.e., divalent metal-ion transporter 1, DMT1). Current efforts of the Knutson lab are to: (i) define the physiologic roles of ZIP14 and ZIP8 in iron metabolism; (ii) determine how ZIP14 and ZIP8 are regulated by iron status; (iii) determine the membrane topology of ZIP14 and ZIP8; (iv) elucidate how ZIP14 and ZIP8 transport iron at the structural and cellular levels; (v) determine if any other ZIP proteins are capable of transporting iron.
ZIP14 appears to play a role in the uptake of non-transferrin-bound iron (NTBI)—a form of iron that appears in the plasma during iron overload. Under normal circumstances, iron in transported in the circulation bound to the plasma protein transferrin. During iron overload, the carrying capacity of transferrin can become exceeded, giving rise to NTBI. NTBI is rapidly taken up by the liver, followed by the kidney, pancreas, heart. Accordingly, NTBI is believed to be a major contributor to iron loading in these tissues, which can become damaged during iron overload. Although we have known about NTBI for over 25 years, the molecular mechanisms that mediate NTBI uptake into cells have remained obscure. In 2006, in collaboration with the laboratory of Dr. Robert J. Cousins, we found that ZIP14 could mediate the uptake of NTBI uptake by cells (1). Moreover, ZIP14 is most abundantly expressed in the liver, pancreas, and heart—the 3 tissues that load iron during iron overload. Detailed studies of iron transport by ZIP14 expressed in Xenopus oocytes (the gold-standard method for assessing transport activity) are consistent with ZIP14 functioning in NTBI uptake (3). We have also found that ZIP14 promotes the assimilation of iron from transferrin (4). Thus, ZIP14 may play two roles in cellular iron acquisition (Figure-1).
ZIP8 is structurally very similar to ZIP14, particularly in transmembrane domains (5). In fact, ZIP8 is most closely related to ZIP14 than any other ZIP family member. In 2012, we reported that ZIP8, similar to ZIP14, can transport iron, making it the third transmembrane iron-import protein to be identified (2). ZIP8 is markedly abundant in the lung, placenta, and pancreas, suggesting that ZIP8 may play important roles in these tissues.
Role of DMT1 in Iron Metabolism. DMT1 is required for the absorption of dietary non-heme iron by the intestine. DMT1 is also required for the uptake of iron by developing erythroid cells of the bone marrow. The role of DMT1 in iron metabolism by other cell types and tissues is less clear. We are using tissue-specific DMT1 knockout mice to determine the role of DMT1 in other tissues important for iron metabolism and/or affected by iron overload.
1. Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci U S A. 2006;103(37):13612-13617. [PubMed]
2. Wang CY, Jenkitkasemwong S, Duarte S, Sparkman B, Shawki A, Mackenzie B, Knutson MD. ZIP8 is an iron and zinc transporter whose cell-surface expression is upregulated by cellular iron loading. J Biol Chem. 2012; 287(41); 34032-34043 Aug 16. [PubMed][2012.Wang et al.JBC - PDF]
3. Pinilla-Tenas JJ, Sparkman BK, Shawki A, Illing AC, Mitchell CJ, Zhao N, Liuzzi JP, Cousins RJ, Knutson MD, Mackenzie B. Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol. 2011;301(4):C862-871. [PubMed]
4. Zhao N, Gao J, Enns CA, Knutson MD. ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J Biol Chem. 2010;285(42):32141-32150. [PubMed]
5. Jenkitkasemwong S, Wang CY, Mackenzie B, Knutson MD. Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals. 2012;25(4):643-655. [PubMed][2012.Jenkitkasemwong et al.Biometals - PDF]