Abstract
Recent studies have shown that the vertebrate magnesium transporters Solute carrier family 41, members 1 and 2 (SLC41A1, SLC41A2) and Magnesium transporter subtype 1 (MagT1) can endow vertebrate B-cells lacking the ion-channel kinase Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) with a capacity to grow and proliferate. SLC41A1 and SLC41A2 display distant homology to the prokaryotic family of Mg2+ transporters, MgtE, first characterized in Bacillus subtilis. These sequence similarities prompted us to investigate whether MgtE could potentially compensate for the lack of TRPM7 in the vertebrate TRPM7-deficient DT40 B-cell model system. Here, we report that overexpression of MgtE is able to rescue the growth of TRPM7-KO DT40 B-cells. However, contrary to a previous report that describes regulation of MgtE channel gating by Mg2+ in a bacterial spheroplast model system, whole cell patch clamp analysis revealed no detectable current development in TRPM7-deficient cells expressing MgtE. In addition, we observed that MgtE expression is strongly downregulated at high magnesium concentrations, similar to what has been described for its vertebrate homolog, SLC41A1. We also show that the N-terminal cytoplasmic domain of MgtE is required for normal MgtE channel function, functionally confirming the predicted importance of this domain in regulation of MgtE-mediated Mg2+ entry. Overall, our findings show that consistent with its proposed function, Mg2+ uptake mediated by MgtE is able to restore cell growth and proliferation of TRPM7-deficient cells and supports the concept of functional homology between MgtE and its vertebrate homologs.
Highlights
The divalent cation magnesium (Mg2+) is required for numerous biological processes and cellular functions in both prokaryotes and eukaryotes
Overexpression of Magnesium transporter subtype 1 (MagT1) has recently been shown to partially rescue the growth impairment defect of TRPM7-KO DT40 B-cells [7] and mutations in the human MAGT1 resulted in a novel X-linked immunodeficiency with magnesium defect, Epstein–Barr virus infection and neoplasia (XMEN) [10,11]
SLC41 family of transporters are distant homologs of the bacterial MgtE proteins, and it has recently been shown that the human SLC41A1 is able to provide growth complementation in Salmonella strain MM281, which lacks any functional magnesium transporters [14]
Summary
The divalent cation magnesium (Mg2+) is required for numerous biological processes and cellular functions in both prokaryotes and eukaryotes. SLC41 family of transporters are distant homologs of the bacterial MgtE proteins, and it has recently been shown that the human SLC41A1 is able to provide growth complementation in Salmonella strain MM281, which lacks any functional magnesium transporters [14]. We showed that SLC41A1 can complement growth of vertebrate TRPM7-deficient (or knockout/KO) cells upon induction and that mutations of the corresponding pore residues in SLC41A1- D263 and D487, led to expression of non-functional transporters which exhibit normal surface trafficking [5]. These data suggested the existence of functional conservation between MgtE and SLC41A1
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