To identify novel genes induced during innate immune activation, we screened a cDNA library prepared from monocytes stimulated with Mycobacterium bovis BCG cell wall. A novel transcript with three-protein coding potential was identified, and the expressed proteins from individual frames showed distinct intracellular localization. Live and heat-killed Mycobacterium, bacterial cell wall, and inflammatory cytokines like TNFalpha were found to be potent inducers of the transcript. Expression of this gene is very low or undetectable in unstimulated monocytes, while a steady expression level was observed during differentiation of monocytes to dendritic cells and macrophages. The entire gene consisted of eight major exons and was localized on chromosome 4q22-q24, spanning approximately 84 kb. The main open reading frame of the transcript encoded a putative seven-transmembrane (TM) protein that showed homology with a number of functionally unknown proteins in the database. Further analysis revealed that all of these proteins have detectable similarity with the ZIP family of metal transporters. In fact, increased accumulation of intracellular Zn(2+) was observed due to the expression of BIGM103 in CHO cells. However, the identified proteins are structurally unique compared to known ZIP members and they also possess the hallmark of Zn-metalloproteases, suggesting a new class of multi-TM protein with dual features. Here we present a collection of these proteins and discuss the functional aspects of BIGM103, based on our results and current findings on two members of the family, Drosophila Catsup and Arabidopsis IAR1.

Zinc is an essential ion for cells with a vital role to play in controlling the cellular processes of the cell, such as growth, development and differentiation. Specialist proteins called zinc transporters control the level of intracellular zinc in cells. In mammals, the ZIP family of zinc transporters has a pivotal role in maintaining the correct level of intracellular zinc by their ability to transport zinc into cells from outside, although they may also transport metal ions other than zinc. There are now recognised to be four subfamilies of the ZIP transporters, including the recently discovered LIV-1 subfamily which has similarity to the oestrogen-regulated gene LIV-1, previously implicated in metastatic breast cancer. We call this new subfamily LZT, for LIV-1 subfamily of ZIP zinc Transporters. Here we document current knowledge of this previously uncharacterised group of proteins, which includes the KE4 proteins. LZT proteins are similar to ZIP transporters in secondary structure and ability to transport metal ions across the plasma membrane or intracellular membranes. However, LZT proteins have a unique motif (HEXPHEXGD) with conserved proline and glutamic acid residues, unprecedented in other zinc transporters. The localisation of LZT proteins to lamellipodiae mirrors cellular location of the membrane-type matrix metalloproteases. These differences to other zinc transporters may be consistent with an alternative role for LZT proteins in cells, particularly in diseases such as cancer.

>sp|Q9C0K1|S39A8_HUMAN Zinc transporter ZIP8 OS=Homo sapiens GN=SLC39A8 PE=1 SV=1
MAPGRAVAGLLLLAAAGLGGVAEGPGLAFSEDVLSVFGANLSLSAAQLQHLLEQMGAASRVGVPEPGQLHFNQCLTAEEI
FSLHGFSNATQITSSKFSVICPAVLQQLNFHPCEDRPKHKTRPSHSEVWGYGFLSVTIINLASLLGLILTPLIKKSYFPK
ILTFFVGLAIGTLFSNAIFQLIPEAFGFDPKVDSYVEKAVAVFGGFYLLFFFERMLKMLLKTYGQNGHTHFGNDNFGPQE
KTHQPKALPAINGVTCYANPAVTEANGHIHFDNVSVVSLQDGKKEPSSCTCLKGPKLSEIGTIAWMITLCDALHNFIDGL
AIGASCTLSLLQGLSTSIAILCEEFPHELGDFVILLNAGMSTRQALLFNFLSACSCYVGLAFGILVGNNFAPNIIFALAG
GMFLYISLADMFPEMNDMLREKVTGRKTDFTFFMIQNAGMLTGFTAILLITLYAGEIELE