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NRAMP1 and 2, MTP1, Duodenal Cytochrome b (Dcytb) Antibodies
Natural resistance to infection with unrelated intracellular parasite such as Mycobacteria, Salmonella, and Leishmania is controlled by a single gene that encodes a macrophage-specific membrane protein designated as Natural Resistance-Associated Macrophage Protein (Nramp1). Naturally occurring and experimentally induced mutations at Nramp1 abrogate natural resistance to infection. Polymorphic variants at the human NRAMP1 locus are associated with differential susceptibility of humans to tuberculosis and leprosy. NRAMP1 is expressed in the lysosomal compartment of monocytes and macrophages, lungs, and spleen. It is induced in response to lymphokines and bacterial products. After phagocytosis, Nramp1 is targeted to the membrane of the microbe-containing phagosome, where it may modify the intraphagosomal milieu to affect microbial infection. Although the physiological role of Nramp1 is unclear, structural predictions suggest that Nramp1 encodes the prototypic member of a transporter family. NRAMP1 (human 550 aa, chromosome 2q35; mouse 548 aa) protein is highly hydrophobic integral membrane glycoproteins composed of 12-transmembrane (TM) domains that possess several structural characteristics of ion channels and transporters. Both N and C-termini are predicted to be cytoplasmic. Recently a second member of NRAMP family, termed NRAMP2/DMT/DCT1 (Divalent Metal ion Transporter 1 or Divalent Cation Transporter 1), has been identified (human, rat and mouse 568 aa, ~65% identity with NRAMP1). Unlike NRAMP1, NRAMP2 expression is more ubiquitous and has been detected in most tissues. However, NRAMP2 expression is more pronounce in brain, thymus, proximal intestine, kidney, and bone marrow. It is dramatically up regulated by iron starvation in the intestine. NRAMP2 gene produces two alternatively spliced transcripts generated by alternative use of two 3' exons encoding distinct C-termini of the protein as well as distinct 3' untranslated regions (UTRs). Interestingly, one Nramp2 mRNA contains an iron-responsive element (IRE) in its 3'UTR. The IRE is an RNA secondary structure present in the 5'- or the 3'-UTR of animal mRNAs encoding proteins involved in iron metabolism. The second Nramp2 splice isoform (without-IRE, isoform II) encodes a protein in which the C-terminal 18-aa of the IRE form (with IRE, isoform I) is replaced by a novel 25-aa segment and codes for a distinct 3' UTR lacking the IRE. The two isoforms are differentially localized and regulated in GI tract and kidney. It has recently been demonstrated that the Nramp2 gene is mutated (Gly185 to Arg at TM4) in both the mk and Belgrade (b) animal models exhibiting a severe microcytic hypochromic anemia marked by a defect in iron absorption by intestinal cells and in erythroid iron use. More recently a novel iron-regulated gene that is homologous to the DMT1, termed Metal Transporter Protein (MTP1, human 571 aa, mouse 570 aa; ~90% similarity), has been identified. MTP1 is also described as iron-regulated transporter (IREG1) and Ferroportin1. MTP1 contains IRE in the 5'-UTR. It is expressed in tissues involved in body iron homeostasis including the developing and mature reticuloendothelial system, the duodenum, and the pregnant uterus. MTP1 is also expressed in muscle and embryonic brain. In the adult mouse, MTP1 expression in the liver and duodenum are reciprocally regulated. Iron deficiency induces MTP1 expression in the duodenum but down-regulates expression in the liver. Therefore, MTP1 may be involved in intracellular iron metabolism. Iron is an essential element for a variety physiological process. A variety of proteins are involved in the transport of iron. Most dietary iron exists in the form of ferric iron complexes which must be reduced to yield ferrous ion before it can be taken up by protein transporters such as DCT1 (divalent cation transporter)/NRAMP2/DMT1. These transporters are especially active in small intestine where most dietary iron absorption is conducted. Ferrous Fe (II) is very unstable at physiological pH and quickly oxidized to ferric Fe (III). Therefore, highly specialized transmembrane electron transport system, maintained by ferric reductases, is required for the availability of intracellular ferrous ion. A number of ferric reductases have been identified in yeast, plants, and bacteria but the identity of such proteins remained unknown in the mammals. Most recently, a new gene called Dcytb (for duodenal cytochrome b) has been cloned and characterized in mouse duodenum that may function as mammalian ferric reductase. Dcytb (human 286 aa,
rat 290 aa) is a 6-transmembrane domains protein with ~45% sequence identity
with cytochrome b561 reductase. However, no sequence homology exists with plant
and yeast Dcytb. The N-terminus of mouse Dcytb is almost identical with the
rabbit's p30 protein called cytochrome b558. Putative biding sites for
cytochrome b561 substrates (ascorbic acid and semidehydroascorbic acid) are
partially conserved in Dcytb and b561. Unlike most proteins involved in iron
metabolism, Dcytb gene lacks a definable iron-responsive element. Dcytb is
highly expressed in the brush border membrane of duodenal entrecotes.
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